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Zhang W, Luo S, Jiang M, Chen Y, Ren R, Wu Y, Wang P, Zhou P, Qin J, Liao W. CSMD1 as a causative gene of developmental and epileptic encephalopathy and generalized epilepsies. Genes Dis 2025; 12:101473. [PMID: 40330149 PMCID: PMC12052674 DOI: 10.1016/j.gendis.2024.101473] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/11/2024] [Accepted: 11/02/2024] [Indexed: 05/08/2025] Open
Abstract
Genetic factors are the major causes of epilepsies, such as developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). However, the etiology of most patients remains elusive. This study performed exon sequencing in a cohort of 173 patients with IGE. Additional cases were recruited from the matching platform in China. The excess and damaging effect of variants, the genotype-phenotype correlation, and the correlation between gene expression and phenotype were studied to validate the gene-disease association. CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE. Additional CSMD1 variants were identified in five cases with DEE featured by generalized seizures from the matching platform, including two with de novo and three with compound heterozygous variants. Two patients were refractory to antiseizure medications and all patients were on long-term therapy. The CSMD1 variants presented a significantly high excess of variants in the case-cohort. Besides de novo origination, the DEE cases had each of the paired variants located closer to each other than the IGE cases or more significant alterations in hydrophobicity. The DEE-associated variants were all absent in the normal population and presented significantly lower minor allele frequency than the IGE-associated variants, suggesting a minor allele frequency-phenotype severity correlation. Gene expression analysis showed that CSMD1 was extensively expressed throughout the brain, particularly in the cortex. The CSMD1 temporal expression pattern correlated with the disease onset and outcomes. This study suggests that CSMD1 is associated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.
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Affiliation(s)
- Wenjun Zhang
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
- School of Medical Laboratory, Shao Yang University, Shaoyang, Hunan 422000, China
| | - Sheng Luo
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
| | - Mi Jiang
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
| | - Yongxin Chen
- Department of Pediatrics, Guangdong General Hospital, Guangzhou, Guangdong 510000, China
| | - Rongna Ren
- Department of Pediatrics, The 900 Hospital of the Joint Service Support Force of the People's Liberation Army of China, Fuzhou, Fujian 350000, China
| | - Yunhong Wu
- Department of Neurology, Children's Hospital of Shanxi, Taiyuan, Shanxi 030000, China
| | - Pengyu Wang
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
| | - Peng Zhou
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
| | - Jiong Qin
- Department of Pediatrics, Peking University People's Hospital, Beijing 100044, China
| | - Weiping Liao
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510000, China
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Clayton LM, Vakrinou A, Balestrini S, Sisodiya SM. Monogenic Epilepsies in Adult Epilepsy Clinics and Gene-Driven Approaches to Treatment. Curr Neurol Neurosci Rep 2025; 25:35. [PMID: 40381056 DOI: 10.1007/s11910-025-01413-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 05/19/2025]
Abstract
PURPOSE OF REVIEW Genetic factors play an important contribution to the aetiology of epilepsy and may have implications for management. Whilst the study of monogenic epilepsies has predominantly centred around children, there is a critical need to understand the burden of monogenic epilepsies in adults. This understanding is essential to steer the application of genetic testing and to facilitate access to gene-driven therapies in adults with epilepsy. RECENT FINDINGS The yield of diagnostic genetic testing in adults with epilepsy and neurodevelopmental disorders is similar to that in children (ranging from 23-50%). Distinct causal genes underlie the most common monogenic epilepsies identified in adulthood compared to childhood, although SCN1A is the most commonly implicated gene across both populations. Genetic diagnoses made in adults with epilepsy frequently have direct implications for clinical management. However, very few gene-driven therapies are supported by evidence from formal studies. Genetic testing should be considered in adults with unexplained epilepsy and may have important implications for management, including the potential for gene-driven therapies. However, further work is needed to understand the outcomes of gene-driven therapies in adults with epilepsy.
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Affiliation(s)
- Lisa M Clayton
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK.
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK.
| | - Angeliki Vakrinou
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - Simona Balestrini
- Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy
- Neuroscience and Medical Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK
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Thanuja B, Kamate M. Genetic Epilepsies With Onset in Infancy and Toddlerhood: A Prospective Single-Center Study in India. Pediatr Neurol 2025; 166:39-46. [PMID: 40088508 DOI: 10.1016/j.pediatrneurol.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/05/2025] [Accepted: 02/04/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND The burden of genetic causes of epilepsy is higher in infants and toddlers. Early diagnosis helps in precision therapy and prenatal diagnosis. The spectrum of genetic causes can vary depending on the location and prevalence of consanguinity practices. METHODS Children having epilepsy with onset before age three years were enrolled after ruling out acquired causes. Neuroimaging, electroencephalography, and whole exome sequencing (WES) were done and seizure outcome was assessed after six months. RESULTS We enrolled 147 participants (82 boys, 65 girls). Mean age at seizure onset was 5.5 ± 6.5 months. WES gave an overall yield of 61.9% (91/147) and 71.4% (40/56) in cases with epilepsy onset before three months. Seventy (76.7%) cases had developmental delay. Commonly implicated genes were SCN1A, KCNQ2, ALDH7A1, STXBP1, TBC1D24, CDKL5, CPLX1, BRAT1, WWOX, and RHOBTB2. The common comorbidities of autism, attention-deficit/hyperactivity disorder, and intellectual disability had a significant association with genetic epilepsy. WES helped in precision medicine in over 40% of cases. While normal development was associated with higher rates of seizure freedom, those with severe microcephaly, a seizure burden of >200/month, or rigidity had higher mortality rates. CONCLUSIONS Genetic etiology for epilepsy is common in children with seizure onset below age three years, with yield being the highest for onset in the first three months. Presence of comorbidities increased the yield of genetic diagnosis. Autosomal recessive disorders are more common in India due to higher consanguinity rates. Higher seizure burden, severe microcephaly, or infantile epileptic spasm syndrome are associated with higher mortality.
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Affiliation(s)
- Basavanagowda Thanuja
- Department of Pediatric Neurology, Jawaharlal Nehru Medical College, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India
| | - Mahesh Kamate
- Department of Pediatric Neurology, Jawaharlal Nehru Medical College, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India.
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Yang Z, Yang C, Huang Z, Xu P, Li Y, Han L, Peng L, Wei X, Pak J, Svitkina T, Schmid SL, Chen Z. CCDC32 stabilizes clathrin-coated pits and drives their invagination. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.26.600785. [PMID: 38979322 PMCID: PMC11230434 DOI: 10.1101/2024.06.26.600785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Clathrin-mediated endocytosis (CME) is essential for maintaining cellular homeostasis. Previous studies have reported more than 50 CME accessory proteins; however, the mechanism driving the invagination of clathrin-coated pits (CCPs) remains elusive. We show by quantitative live cell imaging that siRNA-mediated knockdown of CCDC32, a poorly characterized endocytic accessory protein, leads to the accumulation of unstable flat clathrin assemblies. CCDC32 interacts with the α-appendage domain (AD) of AP2 in vitro and with full length AP2 complexes in cells. Deletion of aa78-98 in CCDC32, corresponding to a predicted α-helix, abrogates AP2 binding and CCDC32's early function in CME. Furthermore, clinically observed nonsense mutations in CCDC32, which result in C-terminal truncations that lack aa78-98, are linked to the development of cardio-facio-neuro-developmental syndrome (CFNDS). Overall, our data demonstrate the function of a novel endocytic accessory protein, CCDC32, in regulating CCP stabilization and invagination, critical early stages of CME. Summary We show that CCDC32, a poorly studied and functionally ambiguous protein, binds to AP2 and regulates CCP stabilization and invagination. Clinically observed mutations in CCDC32 lose their ability to interact with AP2 likely contributing to the development of cardio-facio-neuro-developmental syndrome.
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Chan CK, Lim KS, Chan CY, Kumar TS, Audrey C, Narayanan V, Fong SL, Ng CC. A review of epilepsy syndromes and epileptogenic mechanism affiliated with brain tumor related genes. Gene 2025; 962:149531. [PMID: 40294709 DOI: 10.1016/j.gene.2025.149531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 04/14/2025] [Accepted: 04/23/2025] [Indexed: 04/30/2025]
Abstract
Epilepsy is one of the comorbidities often manifested by patients with brain tumors. While there are reviews commenting on the epileptogenicity of brain-tumor-related genes, the reviews are commonly restricted to BRAF, IDH and PIK3CA. According to World Health Organization (WHO), at least 50 genes have been proposed as brain-tumor-related genes. Hence, we aimed to provide a more comprehensive review of the epileptogenicity of the brain-tumor-related genes. We performed an extensive literature search on PubMed, classified the studies, and provided an overview of the associated epilepsy phenotype and epileptogenic mechanism of the brain-tumor-related genes advocated by WHO. Through our analysis, we found a minor overlap between brain-tumor-related genes and epilepsy-associated genes, as some brain-tumor-related genes have been classified as epilepsy-associated genes in earlier studies. Besides reviewing the well-studied genes like TSC1 and TSC2, we identified several under-discovered brain-tumor-related genes, including TP53, CIC, IDH1 and NOTCH1, that warrant future exploration due to the existence of clinical or in vivo evidence substantiating their pathogenic role in epileptogenesis. We also propounded some methodologies that can be applied in future research to enhance the study of the epileptogenic mechanism of brain-tumor-related genes. To date, this article covers the greatest number of brain-tumor-related genes.
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Affiliation(s)
- Chung-Kin Chan
- Microbiology and Molecular Genetics, Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Kheng-Seang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Chet-Ying Chan
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Thinisha Sathis Kumar
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Christine Audrey
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Vairavan Narayanan
- Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Si-Lei Fong
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Ching-Ching Ng
- Microbiology and Molecular Genetics, Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia.
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van Heurck R, Hammar EB, Ville D, Lebon S, Chatron N, Marconi C, Royer-Bertrand B, Lesca G, Superti-Furga A, Abramowicz M, Korff C. Comprehensive genetic diagnosis and therapeutic perspectives in 155 children with developmental and epileptic encephalopathy. Eur J Paediatr Neurol 2025; 56:97-103. [PMID: 40347601 DOI: 10.1016/j.ejpn.2025.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 03/19/2025] [Accepted: 04/22/2025] [Indexed: 05/14/2025]
Abstract
We studied a retrospective cohort of children with developmental and epileptic encephalopathy (DEE), a group of neurological conditions characterized by early onset epilepsy and severe developmental delay. Cases were recruited from three university hospitals based on clinical criteria, after a blinded cross-validation process, and most were subject to both array-CGH and exome-based gene panel analyses. 155 subjects were included. A genetic diagnosis was identified in 105 (68 %). A majority of patients (71 %) had onset of symptoms before the age of one year. In this age group a disease-causing variant was identified in 73 % of children, the highest proportion of cases reported so far. Genetic heterogeneity was high, involving 40 different genes. The most prevalent gene was SCN1A. Eight genes were identified in multiple patients and accounted for 50 % of all diagnoses. The remaining genes represented ultra-rare disorders. In many cases, molecular diagnosis leads to treatment adaptation and allows for genetic counseling. Those results highlight the growing importance of genetic investigations especially in children with symptoms onset before the age of 1. Finally, we evaluated the disease-causing variants in an intention-to-treat approach and found that almost half would theoretically be amenable to personalized therapy using antisense oligonucleotides (ASOs).
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Affiliation(s)
- R van Heurck
- Genetic Medicine Division, Diagnostics Department, University Hospitals of Geneva, Switzerland
| | - E B Hammar
- Genetic Medicine Division, Diagnostics Department, University Hospitals of Geneva, Switzerland
| | - D Ville
- Pediatric Neurology Department and Reference Center of Rare Epilepsies, University Hospital of Lyon, France
| | - S Lebon
- Pediatric Neurology and Neurorehabilitation Unit, Woman-Mother-Child Department, University Hospital of Lausanne, Lausanne, Switzerland
| | - N Chatron
- Genetic Medicine Division, University Hospitals of Lyon, Lyon, France
| | - C Marconi
- Genetic Medicine Division, Diagnostics Department, University Hospitals of Geneva, Switzerland
| | - B Royer-Bertrand
- Genetic Medicine Division, Lausanne University Hospital of Lausanne, Lausanne, Switzerland
| | - G Lesca
- Genetic Medicine Division, Diagnostics Department, University Hospitals of Lyon, Lyon, France
| | - A Superti-Furga
- Genetica AG, Zurich, and University of Lausanne, Switzerland
| | - M Abramowicz
- Genetic Medicine Division, Diagnostics Department, University Hospitals of Geneva, Switzerland.
| | - C Korff
- Department of the Woman, Child and Adolescent, Pediatric Neurology Unit, University Hospitals of Geneva, Switzerland
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Sun N, Wang X, Huang S, Yang L, Li D. Oxcarbazepine may be an effective option for Chinese pediatric patients with self-limited focal epilepsy of neonatal/infantile onset: a retrospective cohort study. Front Pediatr 2025; 13:1509660. [PMID: 40236662 PMCID: PMC11998760 DOI: 10.3389/fped.2025.1509660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/07/2025] [Indexed: 04/17/2025] Open
Abstract
Objective The aim of this study was to evaluate the long-term follow-up data of Chinese children with self-limited focal epilepsy with neonatal/infantile onset (SeLFE) and to investigate the clinical features, genetic background and treatment outcomes of this type of epileptic syndrome. Methods We conducted a retrospective cohort study of twenty-six children with SeLFE admitted to or followed by the Department of Pediatrics, Second Affiliated Hospital of Xi'an Jiaotong University from October 2011 to October 2021. Treatment decisions were based on the children's seizure semiology, frequency, economy, medication accessibility, allergies and other factors, and initial medications including levetiracetam, phenobarbital and oxcarbazepine. All children were followed up regularly in the outpatient clinic. Results The 26 children, 13 male and 13 female, were followed for a mean of 54.0 (49.0, 58.5) months. Trio whole-exome sequencing (WES) revealed no pathogenic genetic abnormalities in 16 children, and known pathological genes including PRRT2, SCN2A and KCNQ2 were detected in 10 children. Thirteen children (50.0%) achieved complete seizure control after first-line monotherapy. Among the 12 patients who failed to respond to the first monotherapy, 9 patients achieved a seizure free status with oxcarbazepine, which was used as the second-line monotherapy or as add-on therapy. One patient recovered spontaneously without treatment. Conclusion Although SeLFE is often self-limited, this study showed that complete seizure control is not always achieved with initial medication therapy. Oxcarbazepine may be an effective option for the treatment of SeLFE.
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Affiliation(s)
| | | | | | | | - Dan Li
- Department of Paediatrics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Kava H, Akgun-Dogan O, Yesilyurt A, Alanay Y, Isik U. Evaluation of the etiology of epilepsy and/or developmental delay in children via next-generation sequencing: a single-center experience. Front Pediatr 2025; 13:1471965. [PMID: 40083435 PMCID: PMC11904636 DOI: 10.3389/fped.2025.1471965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 01/28/2025] [Indexed: 03/16/2025] Open
Abstract
Background We aimed to understand the genetic etiology in children presenting with epilepsy and/or developmental delay by using next-generation sequencing (NGS). Materials and methods We included children presenting to our pediatric neurology clinic with a diagnosis of epilepsy and/or developmental delay between January 2019 and December 2021. We evaluated the patients using the NGS equipment in our genetic laboratory. Results In total, 90 patients were included in the study. Twenty (34.4%) out of 58 patients who had undergone whole-exome sequencing (WES) had pathogenic or likely pathogenic (P/LP) variants and 11 (18.9%) had variants of unknown significance (VUS). Five (41.6%) out of 12 patients who had undergone whole-genome sequencing had P/LP variants and 5 (41.6%) had VUS. Eleven (55%) out of 20 patients who had undergone WES and chromosomal microarray had P/LP variants and 2 (10%) had VUS. Twenty-six novel variants were described. Twelve patients (13.3%) were diagnosed using a known specific treatment. Conclusion NGS aids in precisely diagnosing children with epilepsy and/or developmental delay. Furthermore, it provides a correct prognosis, specific treatment methods, and a multidisciplinary approach.
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Affiliation(s)
- Handan Kava
- Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
| | - Ozlem Akgun-Dogan
- Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
- Acibadem Mehmet Ali Aydinlar University Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
- Department of Transitional Medicine, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
| | | | - Yasemin Alanay
- Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
- Acibadem Mehmet Ali Aydinlar University Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
- Department of Genome Studies, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
| | - Ugur Isik
- Division of Pediatric Neurology, Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye
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Yalçın Çapan Ö. Navigating Uncertainty: Assessing Variants of Uncertain Significance in the CDKL5 Gene for Developmental and Epileptic Encephalopathy Using In Silico Prediction Tools and Computational Analysis. J Mol Neurosci 2025; 75:19. [PMID: 39945963 DOI: 10.1007/s12031-024-02299-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/06/2024] [Indexed: 04/02/2025]
Abstract
Mutations in the CDKL5 gene are associated with developmental and epileptic encephalopathy (DEE), a severe disorder characterized by developmental delay and epileptic activity. In genetic analyses of DEEs, variants classified as pathogenic confirm the diagnosis of the disease while Variants of Uncertain Significance (VUS) remain in a gray area due to insufficient evidence. This study aimed to optimize the interpretation of VUS in the CDKL5 gene by evaluating the performance of 22 in silico prediction tools using 186 known pathogenic or benign missense variants from the ClinVar database. The best-performing tools were then applied to analyze CDKL5 VUS variants, complemented by the evaluation of evolutionary conservation, structural analyses, and molecular dynamics simulations to assess their impact on protein structure and function. The results identified SNPred as the most reliable tool, achieving 100% accuracy, sensitivity, and specificity. Other high-performing tools, including ESM-1v, AlphaMissense, EVE, and ClinPred, demonstrated over 98% accuracy. Among 44 CDKL5 VUS variants evaluated, 20 were initially classified as pathogenic by these tools. However, further evaluation using stringent criteria-incorporating conservation scores, structural disruptions identified by Missense3D and PyMol, and molecular dynamics simulation results-led to the reclassification of 8 VUS variants as "potentially pathogenic" and the remaining 12 as "variants with conflicting data". This comprehensive approach provides a robust framework for the classification of VUS in the CDKL5 gene, offering critical insights for accurate diagnosis and treatment strategies in DEE. These findings will serve as a valuable resource for clinicians and geneticists in resolving the diagnostic ambiguity associated with VUS.
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Affiliation(s)
- Özlem Yalçın Çapan
- Department of Medical Biology, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Türkiye.
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Best HL, Cook SR, Waller-Evans H, Lloyd-Evans E. Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat. Int J Mol Sci 2025; 26:1471. [PMID: 40003936 PMCID: PMC11855410 DOI: 10.3390/ijms26041471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/31/2025] [Accepted: 02/02/2025] [Indexed: 02/27/2025] Open
Abstract
DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca2+ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients.
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Affiliation(s)
| | | | | | - Emyr Lloyd-Evans
- Medicines Discovery Institute, Main Building, Cardiff University, Cardiff CF10 3AT, UK; (H.L.B.); (S.R.C.); (H.W.-E.)
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Garg D, Chowdhury S, Samineni S, Agarwal A, Srivastava AK. Myoclonus, dystonia and parkinsonism due to a de novo novel variant in the NUS1 gene: Furthering the epilepsy-dyskinesia spectrum. Parkinsonism Relat Disord 2025:107320. [PMID: 39934081 DOI: 10.1016/j.parkreldis.2025.107320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/29/2025] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Affiliation(s)
- Divyani Garg
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
| | - Sampurna Chowdhury
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Sreeja Samineni
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Ayush Agarwal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
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Minere M, Mortensen M, Dorovykh V, Warnes G, Nizetic D, Smart TG, Hannan SB. Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant. Brain 2025; 148:533-548. [PMID: 39028675 PMCID: PMC11788220 DOI: 10.1093/brain/awae232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 04/05/2024] [Accepted: 06/23/2024] [Indexed: 07/21/2024] Open
Abstract
GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbour any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons remains unresolved. Using a range of confocal imaging, flow cytometry, structural modelling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of human embryonic kidney (HEK)-293 T cells and neurons and two-electrode voltage clamping of Xenopus oocytes, we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I and I705N variants. We report that all three point mutations impair neuronal cell surface expression of GABABRs, reducing signalling efficacy. However, a negative effect evident for one variant perturbed neurotransmission by elevating presynaptic Ca2+ signalling. This is reversed by enhancing GABABR signalling via positive allosteric modulation. Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease whilst highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.
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Affiliation(s)
- Marielle Minere
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
| | - Martin Mortensen
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
| | - Valentina Dorovykh
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
| | - Gary Warnes
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Dean Nizetic
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
| | - Trevor G Smart
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
| | - Saad B Hannan
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
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Shim Y, Kim H, Chae JH, Kim KJ, Lim BC. Analysis of initial seizure characteristics in patients with infantile onset genetic epilepsy. Brain Dev 2025; 47:104319. [PMID: 39787995 DOI: 10.1016/j.braindev.2024.104319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/17/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
OBJECTIVE The present study aimed to investigate the initial clinical features of infantile-onset genetic epilepsy and compare initial seizure variables and responses to sodium channel blockers between SCN1A and non-SCN1A group. METHODS We selected 122 patients, comprising 58 patients with SCN1A mutations and 64 patients with mutations in other than SCN1A, from our institutional database. RESULTS Patients identified in the SCN1A group tended to present with fever, prolonged seizure duration, and hemiclonic seizure semiology. Clustering of seizures was found more frequently in patients from the non-SCN1A group. However, an overlap of seizure variables and seizure type in both groups was also noted. While sodium channel blockers aggravated seizures in more than half of the patients (21/29, 72.4 %) in the SCN1A group, the opposite tendency toward a favorable response to sodium channel blockers (19/30, 63.3 %) was found in those in the non-SCN1A group. Notably, no patient showed seizure aggravation after the use of sodium channel blockers in the non-SCN1A group. CONCLUSION This study highlights the need for comprehensive comparative research to guide the management of infantile onset genetic epilepsy patients.
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Affiliation(s)
- Youngkyu Shim
- Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, 123, Jeokgeum-Ro, Danwongu, Ansan-Si, Gyeonggi-do 15355, Republic of Korea
| | - Hunmin Kim
- Department of Pediatrics, Bundang Seoul National University Hospital, 82, Gumi-ro 173beon-Gil, Bundang-Gu, Seongnam-Si, Gyeonggi-Do 13620, Republic of Korea
| | - Jong Hee Chae
- Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehakro, Jongno-Gu, Seoul 03080, Republic of Korea
| | - Ki Joong Kim
- Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehakro, Jongno-Gu, Seoul 03080, Republic of Korea
| | - Byung Chan Lim
- Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehakro, Jongno-Gu, Seoul 03080, Republic of Korea.
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Meng L, Fang Z, Jiang L, Zheng Y, Hong S, Deng Y, Xie L. Heterozygous pathogenic STT3A variation leads to dominant congenital glycosylation disorders and functional validation in zebrafish. Orphanet J Rare Dis 2025; 20:46. [PMID: 39891251 PMCID: PMC11786438 DOI: 10.1186/s13023-025-03557-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/17/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND Congenital disorders of glycosylation are a rare group of disorders characterized by impaired glycosylation, wherein STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex, which is crucial for protein N-glycosylation. Previous studies have reported that STT3A-CDG is caused by autosomal recessive inheritance. However, in this study, we propose that STT3A-CDG can be pathogenic through autosomal dominant inheritance. METHODS The variant was identified via trio whole-exome sequencing. We constructed wild-type and variant plasmids, transfected them into HEK293T cells and detected the expression levels of the STT3A protein. We performed CRISPR-Cas9 to establish heterozygous knockdown zebrafish to validate the functional implications of autosomal dominant inheritance of STT3A in pathogenesis. RESULTS The patient presented with developmental delay, distinctive facial features, short stature, and abnormal discharges. The heterozygous pathogenic missense variant (NM_001278503.2: c.499G > T, NP_001265432.1:p. Asp167Tyr) was identified, and the Western blot results revealed a significant decrease in protein levels. Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology (increased eye distance, increased Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities (reduced number of mineralized bones), developmental delay (reduced adaptability under light‒dark stimuli suggesting abnormal locomotion, orientation, and social behavior), and electrophysiological abnormalities. CONCLUSION We report a proband with a dominant congenital glycosylation disorder caused by heterozygous pathogenic STT3A variation, which is a new inheritance pattern of STT3A. Our report expands the known phenotype of dominant STT3A-CDGs. Furthermore, we provide in vivo validation through the establishment of a heterozygous knockdown zebrafish model for stt3a and strengthened the compelling evidence for dominant STT3A-related pathogenesis.
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Affiliation(s)
- Linxue Meng
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Zhixu Fang
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Li Jiang
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Yinglan Zheng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Siqi Hong
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Yu Deng
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China
| | - Lingling Xie
- Department of Neurology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People's Republic of China.
- National Clinical Research Center for Child Health and Disorders, Chongqing, People's Republic of China.
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People's Republic of China.
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People's Republic of China.
- Chongqing Key Laboratory of Pediatrics, Chongqing, People's Republic of China.
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15
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Tsuneura Y, Matsuki T, Eda S, Hamada N, Harada A, Nagata KI, Nakayama A. Distribution analysis of RAB11A and RAB11B, small GTP-binding proteins, in mice. Mol Biol Rep 2025; 52:178. [PMID: 39883192 DOI: 10.1007/s11033-025-10282-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/21/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND RAB11 is a small GTP-binding protein that regulates intracellular trafficking of recycling endosomes and is thereby involved in several neural functions. Highly similar RAB11 isoforms are encoded by RAB11A and RAB11B genes, and their pathogenic variants are associated with similar neurodevelopmental disorders, suggesting that RAB11A and RAB11B play similar and important roles in brain development. However, the detailed distribution patterns of these isoforms in various organs, including the brain, remain undetermined. METHODS AND RESULTS We generated an antibody against RAB11A and analyzed the distribution of RAB11A and RAB11B in mice. RAB11A was highly expressed in the ovary and the uterus but less abundant in the brain, whereas RAB11B was abundant in the brain, the testis, the ovary, and the uterus. In the developing cortex, RAB11A was enriched in the apical endfeet of apical radial glial cells, whereas RAB11B was abundantly expressed in postmigratory neurons of the cortical plate. In the adult mouse brain, RAB11A and RAB11B were similarly expressed in most neurons, with weak RAB11A signals also observed in the neuropil. In cultured neurons, RAB11A and RAB11B showed only partial co-localization and differential distribution in both soma and neurites. Notably, RAB11A appeared to be more abundant at presynapses than RAB11B. CONCLUSIONS RAB11A and RAB11B exhibit distinct and characteristic distributions in the brain and other organs, suggesting they play different roles throughout the body. In particular, our results suggest they make distinct contributions to cortical development and regulation of the synaptic vesicle cycle.
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Affiliation(s)
- Yumi Tsuneura
- Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 486-0392, Japan
| | - Tohru Matsuki
- Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 486-0392, Japan
| | - Shima Eda
- Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 486-0392, Japan
| | - Nanako Hamada
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 480-0392, Japan
| | - Akihiro Harada
- Department of Cell Biology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan
| | - Koh-Ichi Nagata
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 480-0392, Japan
- Department of Neurochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai- cho, Nagoya, 466-8560, Japan
| | - Atsuo Nakayama
- Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, 486-0392, Japan.
- Department of Neurochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai- cho, Nagoya, 466-8560, Japan.
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16
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Landais R, Strong J, Thomas RH. Case series; NUS1 deletions cause a progressive myoclonic epilepsy with ataxia. Seizure 2025; 124:1-8. [PMID: 39603047 DOI: 10.1016/j.seizure.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/03/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024] Open
Abstract
PURPOSE Mutations in NUS1 cause a neurological congenital glycosylation disorder which encompasses a spectrum from developmental encephalopathy to musculoskeletal, hearing, and visual abnormalities. Pathogenic variants include both point mutations and genomic deletions. We report an adult phenotype of progressive myoclonus epilepsy (PME) and a review of cases with a complete or partial deletion of NUS1. METHODS Our patient, currently age 30, presented with an intellectual disability and developed progressive ataxia with myoclonic tremor, alongside generalised absence and tonic-clonic seizures. At age 28 he was diagnosed with a heterozygous 5.0 Mb deletion of 6q22.1q22.31 involving the NUS1 gene. We are unable to state whether this is a de novo mutation; his mother tested negative for the gene, but his father passed away before any genetic analysis could be performed. Along with the 22 patients reported in published literature, we identified 21 other genetically similar NUS1 deletion variants with sufficient clinical data through ClinVar. RESULTS The identification of NUS1 gene deletion disorder does not lead to a change in treatment but predicts a progressive clinical trajectory. Recognition of this helps differentiate neurological progression from the impact of anti-seizure medicine. CONCLUSION Copy number variants are an often-overlooked cause of PME. We also describe features of psychosis and spasticity and suggest that these may also be due to the NUS1 deletion, expanding the literature that exists on the phenotype of this very rare genetic disorder.
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Affiliation(s)
- Raphaëlle Landais
- Faculty of Medical Sciences, Newcastle University, Newcastle-Upon-Tyne NE1 7RU, United Kingdom.
| | - Jenna Strong
- Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust.
| | - Rhys H Thomas
- Department of Neurology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-Upon-Tyne NE1 4LP, United Kingdom; Translational and Clinical Research Institute, Henry Wellcome Building, Framlington Place, Newcastle-Upon-Tyne NE2 4HH, United Kingdom.
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Kadam SD. Shifting Focus: The "Other" GABAR. Epilepsy Curr 2025; 25:64-66. [PMID: 39659479 PMCID: PMC11626634 DOI: 10.1177/15357597241303613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024] Open
Abstract
Presynaptic Hyperexcitability Reversed by Positive Allosteric Modulation of a GABABR Epilepsy Variant Marielle Minere, Martin Mortensen, Valentina Dorovykh, Gary Warnes, Dean Nizetic, Trevor G Smart, Saad B Hannan. Brain . 2024: awae232. doi/10.1093/brain/awae232/7717204 Gamma-aminobutyric acid B receptors (GABABRs) are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein-coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, and I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbor any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons remains unresolved. Using a range of confocal imaging, flow cytometry, structural modeling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of HEK-293T cells and neurons, and 2-electrode voltage clamping of Xenopus oocytes we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I, and I705N variants.We report that all 3-point mutations impair neuronal cell surface expression of GABABRs, reducing signaling efficacy. However, a negative effect is evident for 1 variant perturbed neurotransmission by elevating presynaptic Ca2+ signaling. This is reversed by enhancing GABABR signaling via positive allosteric modulation.Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease while highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.
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18
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Yang L, Wan X, Hua R, Jiang J, Wang B, Tao R, Wu D. A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient. Ann Clin Transl Neurol 2025; 12:137-148. [PMID: 39737842 PMCID: PMC11752098 DOI: 10.1002/acn3.52262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 10/07/2024] [Accepted: 10/31/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Variants in the GABRA2 gene, which encodes the α2 subunit of the γ-aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clinical presentation and genetic analysis of a Chinese family with a child diagnosed with DEE78, due to a novel GABRA2 variant. METHODS Genetic diagnosis was performed using trio-whole exome sequencing, followed by bioinformatics predictions of pathogenicity. Structural modeling assessed the potential impact of the variant. A mutant plasmid was constructed and transfected into 293 T cells. Western blotting (WB) was used to evaluate mutant protein expression, while co-immunoprecipitation (Co-IP) analyzed interactions with GABRB3 and GABRG2 proteins. Immunofluorescence (IF) assessed the subcellular localization of the mutant protein. RESULTS The 6-year-old male proband presented with seizures starting at age two, along with global developmental delay and hypotonia. Genetic testing revealed a heterozygous de novo variant in GABRA2 gene (NM_000807: c.923C>T, p.Ala308Val). Structural modeling suggested that this variant is located within the extracellular domain, which may disrupt hydrogen bonding interactions with GABRB3 and GABRG2. WB and Co-IP showed reduced protein expression and impaired interactions, potentially destabilizing the pentamer receptor complex. If analysis revealed that the variant did not affect subcellular localization. CONCLUSION This study identified a novel likely pathogenic GABRA2 extracellular domain variant in a Chinese family causing the DEE phenotype. The results expand the genotypic and phenotypic spectrum of GABRA2-related DEE.
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Affiliation(s)
- Li Yang
- Department of Pediatricsthe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiP. R. China
- Department of PediatricsThe People's Hospital of Hanshan CountyHanshanAnhuiP. R. China
| | - Xingyu Wan
- Second School of Clinical MedicineAnhui Medical UniversityHefeiAnhuiP. R. China
| | - Ran Hua
- Department of Pediatricsthe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiP. R. China
| | - Junhong Jiang
- Department of Pediatricsthe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiP. R. China
| | - Baotian Wang
- Department of Pediatricsthe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiP. R. China
| | - Rui Tao
- Department of PsychiatryChaohu Hospital of Anhui Medical UniversityHefeiChina
- Department of Psychiatry, School of Mental Health and Psychological SciencesAnhui Medical UniversityHefeiChina
- Department of PsychiatryAnhui Psychiatric CenterHefeiChina
| | - De Wu
- Department of Pediatricsthe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiP. R. China
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Hsu JY, Ibrahim DH, Ali R, Marchi E, Gavin M, Amble K, Lyon GJ. Novel Copy Number Deletion Involving NUS1 Associated With Epilepsy, Tremor, and Intellectual Disability. Clin Case Rep 2025; 13:e70022. [PMID: 39780902 PMCID: PMC11710847 DOI: 10.1002/ccr3.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 09/03/2024] [Accepted: 11/28/2024] [Indexed: 01/11/2025] Open
Abstract
Copy number variations (CNVs) contribute to various disorders including intellectual disability, developmental disorders, and cancer. This study identifies a de novo 2.62 Mb deletion at 6q22.1_q22.31, implicating the NUS1 gene in epilepsy, spinal abnormalities, and intellectual disability, thereby expanding its known phenotypic associations.
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Affiliation(s)
- Jing Y. Hsu
- Rosalind Franklin University of Medicine and ScienceChicagoIllinoisUSA
- Department of Human GeneticsNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Daniah H. Ibrahim
- Rosalind Franklin University of Medicine and ScienceChicagoIllinoisUSA
- Department of Human GeneticsNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Riza Ali
- Rosalind Franklin University of Medicine and ScienceChicagoIllinoisUSA
- Department of Human GeneticsNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Elaine Marchi
- Department of Human GeneticsNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Maureen Gavin
- George A. Jervis ClinicNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Karen Amble
- George A. Jervis ClinicNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
| | - Gholson J. Lyon
- Department of Human GeneticsNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
- George A. Jervis ClinicNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNew YorkUSA
- The Graduate CenterThe City University of New YorkNew YorkNew YorkUSA
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Mei D, Balestrini S, Parrini E, Gambardella A, Annesi G, De Giorgis V, Gana S, Bassi MT, Zucca C, Elia M, Vetri L, Castellotti B, Ragona F, Mastrangelo M, Pisani F, d'Orsi G, Carella M, Pruna D, Giglio S, Marini C, Cesaroni E, Riva A, Scala M, Licchetta L, Minardi R, Contaldo I, Gambardella ML, Cossu A, Proietti J, Cantalupo G, Trivisano M, De Dominicis A, Specchio N, Tassi L, Guerrini R. National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy. J Med Genet 2024; 62:25-31. [PMID: 39613335 DOI: 10.1136/jmg-2024-110328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period. METHODS Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs. RESULTS We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%). CONCLUSION Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.
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Affiliation(s)
- Davide Mei
- Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCSS, Florence, Italy
| | - Simona Balestrini
- Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCSS, Florence, Italy
- University of Florence, Florence, Italy
| | - Elena Parrini
- Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCSS, Florence, Italy
| | - Antonio Gambardella
- Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi Magna Graecia, Catanzaro, Italy
| | - Grazia Annesi
- Institute for Biomedical Research and Innovation, National Research Council, Cosenza, Italy
| | - Valentina De Giorgis
- Brain and Behavioral Sciences Department, University of Pavia, Pavia, Italy
- Childhood and Adolescence Epilepsy Center, Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy
| | - Simone Gana
- Neurogenetics Research Center, IRCCS Mondino Foundation, ERN EpiCARE Full Member, Pavia, Italy
| | - Maria Teresa Bassi
- Laboratory of Genetics, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Bosisio Parini, Italy
| | - Claudio Zucca
- Clinical Neurophysiology Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy
| | | | - Luigi Vetri
- Oasi Research Institute - IRCCS, Troina, Italy
| | - Barbara Castellotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Francesca Ragona
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Mario Mastrangelo
- Department of Women/Child Health and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Unit of Child Neurology and Psychiatry-Department of Neurosciences/Mental Health, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Rome, Italy
| | - Francesco Pisani
- Unit of Child Neurology and Psychiatry-Department of Neurosciences/Mental Health, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Rome, Italy
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Giuseppe d'Orsi
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - Massimo Carella
- Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - Dario Pruna
- Child Neurology and Epileptology, S. Michele Hospital, ASL Cagliari, Cagliari, Italy
| | - Sabrina Giglio
- Medical Genetics, R. Binaghi Hospital, ASL Cagliari, Cagliari, Italy
| | - Carla Marini
- Child neurology and psychiatric unit, Pediatric Hospital G. Salesi; AOU delle Marche, Ancona, Italy
| | - Elisabetta Cesaroni
- Child neurology and psychiatric unit, Pediatric Hospital G. Salesi; AOU delle Marche, Ancona, Italy
| | - Antonella Riva
- IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genova, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
| | - Marcello Scala
- IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genova, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
| | - Laura Licchetta
- IRCCS Istituto delle Scienze Neurologiche di Bologna, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Full member of the ERN EpiCARE, Bologna, Italy
| | - Raffaella Minardi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Full member of the ERN EpiCARE, Bologna, Italy
| | - Ilaria Contaldo
- Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
| | - Maria Luigia Gambardella
- Child Neurology and Psychiatric Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
| | - Alberto Cossu
- UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Jacopo Proietti
- UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Gaetano Cantalupo
- UOC Neuropsichiatria Infantile, Ospedale della Donna e del Bambino c/o Ospedale Civile Maggiore, AOUI Verona, Full member of ERN EpiCARE, Verona, Italy
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Marina Trivisano
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of ERN EpiCARE, Rome, Italy
| | - Angela De Dominicis
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of ERN EpiCARE, Rome, Italy
| | - Nicola Specchio
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of ERN EpiCARE, Rome, Italy
| | - Laura Tassi
- Claudio Munari Epilepsy Surgery Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Renzo Guerrini
- Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCSS, Florence, Italy
- University of Florence, Florence, Italy
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21
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Liu W, Gao K, Du X, Wen S, Yan H, Wang J, Wang Y, Song C, Lin L, Ji T, Gu W, Jiang Y. SPOUT1 variants associated with autosomal-recessive developmental and epileptic encephalopathy. ACTA EPILEPTOLOGICA 2024; 6:42. [PMID: 40217412 PMCID: PMC11960386 DOI: 10.1186/s42494-024-00185-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 09/12/2024] [Indexed: 01/05/2025] Open
Abstract
BACKGROUND Developmental and epileptic encephalopathy (DEE) is a group of neurodevelopmental disorders characterized by early-onset seizures predominantly attributed to genetic causes. Nevertheless, numerous patients remain without identification of a genetic cause. METHODS We present four unrelated Chinese patients with SPOUT1 compound heterozygous variants, all of whom were diagnosed with DEE. We also investigated functions of SPOUT1 using the spout1 knockout zebrafish model. RESULTS The four unrelated DEE patients with SPOUT1 compound heterozygous variants were all males. Their onset age of seizure ranged from 3 months to 6 months (median age 5 months). All patients had epileptic spasms, and were diagnosed with infantile epileptic spasms syndrome (IESS). Three patients had microcephaly during infancy. Brain MRI in three patients showed white matter hypomyelination and bilaterally widened frontotemporal subarachnoid space. At the last follow-up, two patients exhibited drug-resistant epilepsy, one achieved seizure freedom following vigabatrin treatment, and one died at the age of 4 years and 5 months from probable sudden unexpected death in epilepsy. Seven different SPOUT1 variants were identified in the four patients, including six missense variants and one deletion variant. AlphaFold2 prediction indicated that all variants alternated the number or the length of bonds between animo acids in protein SPOUT1. Neurophysiological results from spout1 knockout zebrafish revealed the presence of epileptiform signals in 9 out of 63 spout1 knockout zebrafishes (P = 0.009). Transcriptome sequencing revealed 21 differentially expressed genes between spout1 knockout and control groups, including 13 up-regulated and 8 down-regulated genes. Two axonal transport-related genes, kif3a and ap3d1, were most prominently involved in enriched Gene Ontology (GO) terms. CONCLUSIONS This study identified SPOUT1 as a novel candidate gene of DEE, which follows the autosomal-recessive inheritance pattern. IESS is the most common epilepsy syndrome. Downregulation of axonal transport-related genes, KIF3A and AP3D1, may play a crucial role in the pathogenesis of DEE.
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Affiliation(s)
- Wenwei Liu
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
| | - Kai Gao
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100009, China
- Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, 100176, China
| | - Xilong Du
- Beijing Chigene Translational Medical Research Center Co. Ltd, Beijing, 101121, China
| | - Sijia Wen
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
| | - Huifang Yan
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
| | - Jingmin Wang
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100009, China
| | - Yong Wang
- Department of Pediatrics, Fujian Medical University Union Hospital, Fujian, 350001, China
| | - Conglei Song
- Department of Neurology, Anhui Children's Hospital, Anhui, 230051, China
| | - Li Lin
- Department of Neurology, Anhui Children's Hospital, Anhui, 230051, China
| | - Taoyun Ji
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China
| | - Weiyue Gu
- Beijing Chigene Translational Medical Research Center Co. Ltd, Beijing, 101121, China
| | - Yuwu Jiang
- Children's Medical Center, Peking University First Hospital, Beijing, 100176, China.
- Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, 100009, China.
- Children Epilepsy Center, Peking University First Hospital, Beijing, 100176, China.
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100009, China.
- Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, 100176, China.
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22
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Sveistrup MA, Myers KA. Mosaic CLTC pathogenic variant causing focal epilepsy with normal intelligence. Epileptic Disord 2024; 26:875-878. [PMID: 39235893 PMCID: PMC11651378 DOI: 10.1002/epd2.20270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/26/2024] [Accepted: 08/01/2024] [Indexed: 09/07/2024]
Affiliation(s)
| | - Kenneth A. Myers
- Child Health & Human Development ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
- Division of Neurology, Department of PediatricsMontreal Children's Hospital, McGill University Health CentreMontrealQuebecCanada
- Department of Neurology and NeurosurgeryMontreal Children's Hospital, McGill University Health CentreMontrealQuebecCanada
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23
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de Oliveira Franco Á, Morillos MB, Bravo Leite MT, Bianchin MM, Torres CM. DHDDS-related epilepsy with hippocampal atrophy: a case report. Neurogenetics 2024; 26:3. [PMID: 39576357 DOI: 10.1007/s10048-024-00780-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 11/05/2024] [Indexed: 11/24/2024]
Abstract
Developmental delay and seizures with or without movement abnormalities (DEDSM) is a neurodevelopmental phenotype associated with monoallelic mutations in the DHDDS gene. We report a novel case of DEDSM linked to a DHDDS variant (c.614G > A, p.Arg205Gln) in a 45-year-old Brazilian patient presenting with refractory epilepsy, ataxia, dystonia, parkinsonism, and global developmental delay. This is the first case to associate a DHDDS variant with hippocampal atrophy on neuroimaging. After adjustments in anticonvulsant therapy, seizure control was achieved, and the patient-who was previously unable to walk due to frequent falls attributed to myoclonic jerks-showed significant improvement in gait and mobility.
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Affiliation(s)
- Álvaro de Oliveira Franco
- Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350 Rua Ramiro Barcelos, Porto Alegre, RS, 90035-903, Brazil.
- Postgraduate Research Program in Biological Sciences, Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Matheus Bernardon Morillos
- Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350 Rua Ramiro Barcelos, Porto Alegre, RS, 90035-903, Brazil
- Postgraduate Research Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Martim Tobias Bravo Leite
- Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350 Rua Ramiro Barcelos, Porto Alegre, RS, 90035-903, Brazil
| | - Marino Muxfeldt Bianchin
- Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350 Rua Ramiro Barcelos, Porto Alegre, RS, 90035-903, Brazil
- Postgraduate Research Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- CETER, Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carolina Machado Torres
- Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 2350 Rua Ramiro Barcelos, Porto Alegre, RS, 90035-903, Brazil
- Postgraduate Research Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- CETER, Service of Neurology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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24
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Surdi P, Trivisano M, De Dominicis A, Mercier M, Piscitello LM, Pavia GC, Calabrese C, Cappelletti S, Correale C, Mazzone L, Vigevano F, Specchio N. Unveiling the disease progression in developmental and epileptic encephalopathies: Insights from EEG and neuropsychology. Epilepsia 2024; 65:3279-3292. [PMID: 39287605 DOI: 10.1111/epi.18127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
OBJECTIVE Developmental and epileptic encephalopathies (DEEs) are neurological disorders characterized by developmental impairment and epilepsy. Our study aims to assess disease progression by comparing clinical findings, electroencephalography (EEG), and neuropsychological data from seizure onset to the last follow-up evaluation. METHODS We retrospectively reviewed patients with genetic DEEs who were followed-up at the epilepsy unit of Bambino Gesù Children's Hospital, Rome. We collected information regarding gender, family history, genetic variant, age at onset and at last follow-up, neurological examination, type of seizure, drug resistance, occurrence of status epilepticus, and movement and cognitive and behavioral disorders. We compared EEG background activity, epileptiform abnormalities, and cognitive functions between seizure onset and the last follow-up evaluation using the McNemar-Bowker test (α = 5%). RESULTS A total of 160 patients (94 female) were included. Genetic analysis revealed a spectrum of pathogenic variants, with SCN1A being the most prevalent (25%). The median age at seizure onset and at the last follow-up was 0.37 (interquartile range [IQR]: 0.09-0.75) and 8.54 years (IQR: 4.32-14.55), respectively. We documented a statistically significant difference in EEG background activity (p = .017) and cognitive impairment (p = .01) from seizure onset to the last follow-up evaluation. No significant differences were detected for epileptiform abnormalities (p = .2). In addition, high prevalence rates were observed for drug resistance (81.9%), movement disorders (60.6%), behavioral and autism spectrum disorders (45%), neurological deficits (31.3%), and occurrence of status epilepticus (23.1%). SIGNIFICANCE Our study provides evidence that a clinical progression may appear in genetic DEEs, manifesting as development or worsening of cognitive impairment and disruption of EEG background activity. These results highlight the challenging clinical course and the importance of early intervention and personalized care in the management of patients with DEEs.
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Affiliation(s)
- Paolo Surdi
- Child Neurology and Psychiatry Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy
| | - Marina Trivisano
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Angela De Dominicis
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Mattia Mercier
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Ludovica Maria Piscitello
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Giusy Carfì Pavia
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Costanza Calabrese
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Simona Cappelletti
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Cinzia Correale
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
| | - Luigi Mazzone
- Child Neurology and Psychiatry Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy
| | - Federico Vigevano
- Pediatric Neurorehabilitation Department, IRCCS San Raffaele, Rome, Italy
| | - Nicola Specchio
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Rome, Italy
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25
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Borroto MC, Patel H, Srivastava S, Swanson LC, Keren B, Whalen S, Mignot C, Wang X, Chen Q, Rosenfeld JA, McLean S, Littlejohn RO, Emrick L, Burrage LC, Attali R, Lesca G, Acquaviva-Bourdain C, Sarret C, Seaver LH, Platzer K, Bartolomaeus T, Wünsch C, Fischer S, Rodriguez Barreto AM, Granadillo JL, Schreiner E, Brunet T, Schatz UA, Thiffault I, Mullegama SV, Michaud JL, Hamdan FF, Rossignol E, Campeau PM. Cohort Expansion and Genotype-Phenotype Analysis of RAB11A-Associated Neurodevelopmental Disorder. Pediatr Neurol 2024; 160:45-53. [PMID: 39181022 DOI: 10.1016/j.pediatrneurol.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 11/07/2023] [Accepted: 07/13/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations. METHODS We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate. RESULTS We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype. CONCLUSIONS Similar to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites.
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Affiliation(s)
| | - Heena Patel
- Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada
| | - Siddharth Srivastava
- Department of Neurology, Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lindsay C Swanson
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts
| | - Boris Keren
- Département de génétique, APHP-Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Sandra Whalen
- UF de Génétique Clinique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs, APHP, Sorbonne Université, Hôpital Trousseau, Paris, France
| | - Cyril Mignot
- Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau, APHP, Sorbonne Université, Paris, France
| | | | - Qian Chen
- Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Scott McLean
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | - Rebecca O Littlejohn
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas
| | - Lisa Emrick
- Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Ruben Attali
- Genomic Research Department, Emedgene, an Illumina Company, Tel Aviv, Israel
| | - Gaetan Lesca
- Department of Medical Genetics, Lyon University Hospital, University Claude Bernard Lyon 1, Lyon, France
| | - Cecile Acquaviva-Bourdain
- Hospices civils de Lyon, service biochimie et biologie moléculaire, UF maladies héréditaires du métabolisme, Bron, France
| | - Catherine Sarret
- CHU Estaing, Pôle Pédiatrie, Service de Génétique, Clermont-Ferrand, France
| | - Laurie H Seaver
- Corewell Health Helen DeVos Children's Hospital, Grand Rapids, Michigan; Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Grand Rapids, Michigan
| | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Tobias Bartolomaeus
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Cornelia Wünsch
- Sozialpädiatrisches Zentrum Leipzig - Frühe Hilfe Leipzig e.V., Leipzig, Germany
| | - Susann Fischer
- Sozialpädiatrisches Zentrum Leipzig - Frühe Hilfe Leipzig e.V., Leipzig, Germany
| | | | - Jorge L Granadillo
- Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Elisabeth Schreiner
- Diagnostic and Research Institute of Human Genetics, Medical University of Graz, Graz, Austria
| | - Theresa Brunet
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, LMU - University of Munich, Munich, Germany
| | - Ulrich A Schatz
- Institute of Human Genetics, Technical University of Munich, Munich, Germany
| | - Isabelle Thiffault
- Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, Missouri
| | | | - Jacques L Michaud
- Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada; Departments of Pediatrics and Neurosciences, Université de Montréal, Montreal, Québec, Canada
| | - Fadi F Hamdan
- Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada; Department of Pediatrics, University of Montreal, Montreal, Québec, Canada
| | - Elsa Rossignol
- Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada
| | - Philippe M Campeau
- Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada; Department of Pediatrics, University of Montreal, Montreal, Québec, Canada.
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26
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Knowles JK, Warren AEL, Mohamed IS, Stafstrom CE, Koh HY, Samanta D, Shellhaas RA, Gupta G, Dixon‐Salazar T, Tran L, Bhatia S, McCabe JM, Patel AD, Grinspan ZM. Clinical trials for Lennox-Gastaut syndrome: Challenges and priorities. Ann Clin Transl Neurol 2024; 11:2818-2835. [PMID: 39440617 PMCID: PMC11572735 DOI: 10.1002/acn3.52211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 09/05/2024] [Indexed: 10/25/2024] Open
Abstract
OBJECTIVE Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. METHODS The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. RESULTS We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease-modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient-centered outcomes, using emerging measures adapted to people with LGS. INTERPRETATION Clinicians and researchers should enact these priorities, with the goal of patient-centered clinical trials that are tailored to LGS pathophysiology and natural history.
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Affiliation(s)
- Juliet K. Knowles
- Department of NeurologyStanford University School of MedicineStanfordCaliforniaUSA
| | - Aaron E. L. Warren
- Department of NeurosurgeryBrigham and Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | | | - Carl E. Stafstrom
- Department of NeurologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Hyun Yong Koh
- Department of Pediatrics, Section of Neurology and Developmental NeuroscienceBaylor College of MedicineHoustonTexasUSA
| | - Debopam Samanta
- Department of PediatricsUniversity of Arkansas for Medical SciencesLittle RockArkansasUSA
| | - Renée A. Shellhaas
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Gita Gupta
- Department of PediatricsUniversity of MichiganAnn ArborMichiganUSA
| | | | - Linh Tran
- Jane and John Justin Institute for Mind HealthCook Children's Medical CenterFort WorthTexasUSA
| | - Sonal Bhatia
- Division of Pediatric NeurologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | | | - Anup D. Patel
- Department of PediatricsThe Ohio State University College of MedicineColumbusOhioUSA
- The Center for Clinical ExcellenceNationwide Children's HospitalColumbusOhioUSA
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Marques P, Moloney PB, Ji C, Zulfiqar Ali Q, Ramesh A, Goldstein DB, Barboza K, Chandran I, Rong M, Selvarajah A, Qaiser F, Lira VST, Valiante TA, Bazil CW, Choi H, Devinsky O, Depondt C, O'Brien T, Perucca P, Sen A, Dugan P, Sands TT, Delanty N, Andrade DM. Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy? Epilepsy Res 2024; 206:107425. [PMID: 39168079 DOI: 10.1016/j.eplepsyres.2024.107425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/24/2024] [Accepted: 08/05/2024] [Indexed: 08/23/2024]
Abstract
OBJECTIVE We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48 %), compared with the RS group (14 %) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47 %) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71 % versus 41 % with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65 %) having ≥50 % seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.
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Affiliation(s)
- Paula Marques
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - Caihong Ji
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Quratulain Zulfiqar Ali
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Archana Ramesh
- Oxford Epilepsy Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - David B Goldstein
- Institute for Genomic Medicine, Columbia University, New York, NY, USA
| | - Karen Barboza
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ilakkiah Chandran
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Marlene Rong
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Arunan Selvarajah
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Farah Qaiser
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Victor S T Lira
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Taufik A Valiante
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Carl W Bazil
- Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Hyunmi Choi
- Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Orrin Devinsky
- New York University Langone Health Comprehensive Epilepsy Center, New York, NY, USA
| | - Chantal Depondt
- Department of Neurology, CUB Erasme Hospital, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium
| | - Terence O'Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Piero Perucca
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Melbourne, Victoria, Australia; Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Melbourne, Victoria, Australia
| | - Arjune Sen
- Oxford Epilepsy Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Patricia Dugan
- New York University Langone Health Comprehensive Epilepsy Center, New York, NY, USA
| | - Tristan T Sands
- Department of Neurology, Columbia University Medical Center, New York, NY, USA.
| | - Norman Delanty
- Department of Neurology, Beaumont Hospital, Dublin, Ireland.
| | - Danielle M Andrade
- Adult Genetic Epilepsy (AGE) Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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Sirchia F, Taietti I, Donesana M, Bassanese F, Clemente AM, Barbato E, Orsini A, Ferretti A, Marseglia GL, Savasta S, Foiadelli T. Expanding the Spectrum of Autosomal Dominant ATP6V1A-Related Disease: Case Report and Literature Review. Genes (Basel) 2024; 15:1219. [PMID: 39336810 PMCID: PMC11431710 DOI: 10.3390/genes15091219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/13/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Developmental and epileptic encephalopathies (DEE) are a group of disorders often linked to de novo mutations, including those in the ATP6V1A gene. These mutations, particularly dominant gain-of-function (GOF) variants, have been associated with a spectrum of phenotypes, ranging from severe DEE and infantile spasms to milder conditions like autism spectrum disorder and language delays. METHODS We aim to expand ATP6V1A-related disease spectrum by describing a six-year-old boy who presented with a febrile seizure, mild intellectual disability (ID), language delay, acquired microcephaly, and dysmorphic features. RESULTS Genetic analysis revealed a novel de novo heterozygous pathogenic variant (c.82G>A, p.Val28Met) in the ATP6V1A gene. He did not develop epilepsy, and neuroimaging remained normal over five years of follow-up. Although ATP6V1A mutations have traditionally been linked to severe neurodevelopmental disorders, often with early-onset epilepsy, they may exhibit milder, non-progressive phenotypes, challenging previous assumptions about the severity of ATP6V1A-related conditions. CONCLUSIONS This case expands the known clinical spectrum, illustrating that not all patients with ATP6V1A mutations exhibit severe neurological impairment or epilepsy and underscoring the importance of including this gene in differential diagnoses for developmental delays, especially when febrile seizures or dysmorphic features are present. Broader genotype-phenotype correlations are essential for improving predictive accuracy and guiding clinical management, especially as more cases with mild presentations are identified.
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Affiliation(s)
- Fabio Sirchia
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
- Medical Genetics Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Ivan Taietti
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Myriam Donesana
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Francesco Bassanese
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Andrea Martina Clemente
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Eliana Barbato
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Alessandro Orsini
- Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Pisa, 56100 Pisa, Italy;
| | - Alessandro Ferretti
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, 00189 Rome, Italy;
| | - Gian Luigi Marseglia
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Salvatore Savasta
- Pediatric Clinic and Rare Diseases, P.O. Pediatrico Microcitemico “A. Cao”, Università degli Studi di Cagliari, 09121 Cagliari, Italy;
| | - Thomas Foiadelli
- Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; (M.D.); (F.B.); (A.M.C.); (E.B.); (G.L.M.); (T.F.)
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Charouf D, Miller D, Haddad L, White FA, Boustany RM, Obeid M. High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study. Int J Mol Sci 2024; 25:9645. [PMID: 39273593 PMCID: PMC11395515 DOI: 10.3390/ijms25179645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.
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Affiliation(s)
- Daniel Charouf
- Division of Child Neurology, Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Riad El Solh, Beirut P.O. Box 11-0236, Lebanon
| | - Derryl Miller
- Division of Child Neurology, Department of Neurology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN 46202, USA
| | - Laith Haddad
- Division of Child Neurology, Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Riad El Solh, Beirut P.O. Box 11-0236, Lebanon
| | - Fletcher A White
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rose-Mary Boustany
- Division of Child Neurology, Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Riad El Solh, Beirut P.O. Box 11-0236, Lebanon
- Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon
| | - Makram Obeid
- Division of Child Neurology, Department of Pediatric and Adolescent Medicine, American University of Beirut Medical Center, Riad El Solh, Beirut P.O. Box 11-0236, Lebanon
- Division of Child Neurology, Department of Neurology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN 46202, USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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30
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Scheffer IE, Zuberi S, Mefford HC, Guerrini R, McTague A. Developmental and epileptic encephalopathies. Nat Rev Dis Primers 2024; 10:61. [PMID: 39237642 DOI: 10.1038/s41572-024-00546-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 09/07/2024]
Abstract
Developmental and epileptic encephalopathies, the most severe group of epilepsies, are characterized by seizures and frequent epileptiform activity associated with developmental slowing or regression. Onset typically occurs in infancy or childhood and includes many well-defined epilepsy syndromes. Patients have wide-ranging comorbidities including intellectual disability, psychiatric features, such as autism spectrum disorder and behavioural problems, movement and musculoskeletal disorders, gastrointestinal and sleep problems, together with an increased mortality rate. Problems change with age and patients require substantial support throughout life, placing a high psychosocial burden on parents, carers and the community. In many patients, the aetiology can be identified, and a genetic cause is found in >50% of patients using next-generation sequencing technologies. More than 900 genes have been identified as monogenic causes of developmental and epileptic encephalopathies and many cell components and processes have been implicated in their pathophysiology, including ion channels and transporters, synaptic proteins, cell signalling and metabolism and epigenetic regulation. Polygenic risk score analyses have shown that common variants also contribute to phenotypic variability. Holistic management, which encompasses antiseizure therapies and care for multimorbidities, is determined both by epilepsy syndrome and aetiology. Identification of the underlying aetiology enables the development of precision medicines to improve the long-term outcome of patients with these devastating diseases.
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Affiliation(s)
- Ingrid E Scheffer
- Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
- Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia.
- Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
| | - Sameer Zuberi
- Paediatric Neurosciences Research Group, School of Health & Wellbeing, University of Glasgow, Glasgow, UK
- Paediatric Neurosciences, Royal Hospital for Children, Glasgow, UK
| | - Heather C Mefford
- Center for Paediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Renzo Guerrini
- Neuroscience Department, Children's Hospital Meyer IRCCS, Florence, Italy
- University of Florence, Florence, Italy
| | - Amy McTague
- Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
- Department of Neurology, Great Ormond Street Hospital, London, UK
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31
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Muffels IJJ, Sadek M, Kozicz T, Morava E. Assessing age of onset and clinical symptoms over time in patients with heterozygous pathogenic DHDDS variants. J Inherit Metab Dis 2024; 47:935-944. [PMID: 39540616 DOI: 10.1002/jimd.12769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/06/2024] [Accepted: 06/03/2024] [Indexed: 11/16/2024]
Abstract
Mono-allelic DHDDS variants are associated with seizures, intellectual disability, and movement disorders. The age of onset and progression rates of symptoms vary greatly among patients, spanning from infancy to late adulthood. Yet, the reasons behind this clinical variability and the underlying pathophysiological mechanisms of the disease have remained elusive. We investigated the age of onset and the progression of symptoms over time in 59 patients with heterozygous DHDDS variants, drawing from medical literature and incorporating five previously unreported cases from the FCDGC Natural History Study. Clinical symptoms typically emerged early in life. Ataxia, tremor, dystonia, and dyskinesia manifested slightly later in childhood. Global developmental delay usually presented as the initial symptom. We observed diverse rates of symptom accumulation over time: some patients exhibited the full spectrum of symptoms in early childhood, while others developed novel symptoms well into adulthood. Interestingly, neither the sex nor the underlying DHDDS variants correlated with the age of symptom onset or specific clinical symptoms. Additionally, we found that 19% of patients presented with autism spectrum disorder. This study offers insight into the age of symptom onset and the rate of symptom accumulation in patients with DHDDS variants. We found no correlation between the age of onset and progression of clinical symptoms with specific DHDDS variants or patient sex. Autism spectrum disorder is common in patients and warrants attention in clinical management.
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Affiliation(s)
- I J J Muffels
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - M Sadek
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - T Kozicz
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Anatomy, University of Pecs Medical School, Pecs, Hungary
| | - E Morava
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Biophysics, University of Pecs Medical School, Pecs, Hungary
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32
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Ma J, Zhang H, Lv Y, Gao M, Gai Z, Liu Y. Clinical and Genetic Characteristics of Two Cases With Developmental and Epileptic Encephalopathy 93 Caused by Novel ATP6V1A Mutations and Literature Review. Hum Mutat 2024; 2024:4678670. [PMID: 40225911 PMCID: PMC11919110 DOI: 10.1155/2024/4678670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 05/07/2024] [Accepted: 06/29/2024] [Indexed: 01/05/2025]
Abstract
Developmental and epileptic encephalopathy 93 (DEE93) is a new defined autosomal dominant neurologic disorder caused by heterozygous mutations in the ATP6V1A gene on chromosome 3q13. DEE93 is characterized by developmental delay, early-onset refractory seizures, hypotonia, and intellectual disability. So far, merely 31 cases caused by ATP6V1A gene mutation have been reported in literature worldwide, and early genetic detection is required for differential diagnosis. Here, we analyze the clinical and genetic features of two patients with two novel ATP6V1A mutations (c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu)) and expound the therapeutic schedule for epilepsy. We also review the reported mutations and genotypes associated with the disorder. Our study expands the clinical and genetic spectrum of ATP6V1A mutation-associated DEE93, which provides a basis for the diagnosis, treatment, and genetic counseling of the disorder.
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Affiliation(s)
- Jian Ma
- Pediatric Research InstituteChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
| | - Hongwei Zhang
- Pediatric Neurology DepartmentChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
| | - Yuqiang Lv
- Pediatric Research InstituteChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
| | - Min Gao
- Pediatric Research InstituteChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
| | - Zhongtao Gai
- Pediatric Research InstituteChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
- Shandong Provincial Clinical Research Center for Children's Health and Disease, Jinan, China
| | - Yi Liu
- Pediatric Research InstituteChildren's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
- Shandong Provincial Clinical Research Center for Children's Health and Disease, Jinan, China
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Li PP, Zhou YY, Gao L, Lv JN, Xu SS, Zhao YW, Xu D, Huang R, Zhang X, Li P, Fu X, He Z. The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABA AR function. Neuroscience 2024; 553:172-184. [PMID: 38964454 DOI: 10.1016/j.neuroscience.2024.06.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABAAR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABAAR containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.
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Affiliation(s)
- Ping-Ping Li
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yue-Yuan Zhou
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Li Gao
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jia-Nan Lv
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Shi-Shi Xu
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yan-Wen Zhao
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Di Xu
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Ruoke Huang
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Xiong Zhang
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Peijun Li
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China
| | - Xiaoqin Fu
- Department of Geriatrics and Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China
| | - Zhiyong He
- Department of Pediatric Rehabilitation, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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34
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Zhu X, Li P. GABA(A) Receptor Subunit (γ2, δ, β1-3) Variants in Genetic Epilepsy: A Comprehensive Summary of 206 Clinical Cases. J Child Neurol 2024; 39:354-370. [PMID: 39228214 DOI: 10.1177/08830738241273437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Epilepsy is identified in individuals who experienced 2 or more unprovoked seizures occurring over 24 hours apart, which can have a profound impact on a person's neurobiological, cognitive, psychological, and social well-being. Epilepsy is considerably diverse, with classifications such as genetic epilepsy that result directly from a known or presumed genetic variant with the core symptoms of seizures. The GABAA receptor primarily functions as a heteropentamer, containing 3 of 8 subunit types: α, β, γ, δ, ε, π, θ, and ρ. In the adult brain, the GABAA receptor is the primary inhibitory component in neural networks. The involvement of GABAA receptors in the pathogenesis of epilepsy has been proposed. We extensively reviewed all relevant clinical data of previously published cases of GABAA receptor subunit γ2, δ, β1-3 variants included in PubMed up to February 2024, including the variant types, loci, postulated mechanisms, their relevant regions, first onset ages, and phenotypes. We summarized the postulated mechanisms of epileptic pathogenesis. We also divided the collected 206 cases of epilepsy into 4 epileptic phenotypes: genetic generalized epilepsies, focal epilepsy, developmental and epileptic encephalopathies, and epilepsy with fever sensibility. We showed that there were significant differences in the likelihood of the γ2, β2, and β3 subunit variants causing genetic generalized epilepsies, focal epilepsy, developmental and epileptic encephalopathies, and epilepsy with fever sensibility. Patients with the β3 subunit variant seemed related to an earlier first onset age. Our review supports that GABAA receptor subunit variants are a crucial area of epilepsy research and treatment exploration.
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Affiliation(s)
- Xinyi Zhu
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Peijun Li
- Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Furley K, Hunter MF, Fahey M, Williams K. Diagnostic findings and yield of investigations for children with developmental regression. Am J Med Genet A 2024; 194:e63607. [PMID: 38536866 DOI: 10.1002/ajmg.a.63607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/11/2024] [Accepted: 03/13/2024] [Indexed: 07/05/2024]
Abstract
Childhood conditions that feature developmental regression are poorly understood. Phenotype-genotype characterization and diagnostic yield data are needed to inform clinical decision-making. The aim of this study was to report the conditions featuring developmental regression and assess diagnostic yields of investigations. A retrospective chart review of children presenting with developmental regression to a tertiary pediatric genetic clinic between 2018 and 2021 was performed. Of 99 children, 30% (n = 30) had intellectual disability (ID), 21% (n = 21) were autistic, 39% (n = 39) were autistic with ID, and 9% (n = 9) did not have ID or autism. Thirty-two percent (n = 32) of children received a new diagnosis, including eight molecular findings not previously reported to feature developmental regression. Of the children investigated, exome sequencing (ES) provided the highest diagnostic yield (51.1%, n = 24/47), highest (63.6%, n = 14/22) for children with ID, 50% for autistic children with ID (n = 6/12) and children without autism or ID (n = 3/6), and 14.3% (n = 1/7) for autistic children without ID. We highlight the conditions that feature developmental regression and report on novel phenotypic expansions. The high diagnostic yield of ES, regardless of autism or ID diagnosis, indicates the presence of developmental regression as an opportunity to identify the cause, including for genetic differences not previously reported to include regression.
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Affiliation(s)
- Kirsten Furley
- Department of Paediatrics, Monash University, Melbourne, Australia
- Monash Children's Hospital, Melbourne, Australia
| | - Matthew F Hunter
- Department of Paediatrics, Monash University, Melbourne, Australia
- Monash Genetics, Monash Health, Melbourne, Australia
| | - Michael Fahey
- Department of Paediatrics, Monash University, Melbourne, Australia
- Monash Children's Hospital, Melbourne, Australia
- Neurology, Monash Health, Melbourne, Australia
| | - Katrina Williams
- Department of Paediatrics, Monash University, Melbourne, Australia
- Monash Children's Hospital, Melbourne, Australia
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Frye RE. Editorial: Mitochondrial Gene Variations Increase Autism Risk: Uncovering the Complex Polygenetic Landscape of Autism. J Am Acad Child Adolesc Psychiatry 2024; 63:775-777. [PMID: 38072246 DOI: 10.1016/j.jaac.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023]
Abstract
Autism spectrum disorder (ASD) is a behaviorally defined disorder with a complex, mostly unknown, etiology. Although many neurodevelopmental genetic disorders are associated with ASD, single gene mutations and copy number variations do not account for the majority of ASD cases. In fact, when found, genetic alterations are usually de novo rather than inherited.1 Scientists are starting to consider polygenetic influences in the etiology of ASD whereby changes in multiple genes might add up to a threshold that disrupts cellular pathways. Further studies have implicated many environmental factors, particularly the prenatal maternal environment, suggesting that many cases of ASD might be associated with complex interactions between polygenetic predisposition and environmental factors.2.
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Affiliation(s)
- Richard E Frye
- Dr. Frye is with Autism Discovery and Treatment Foundation, Phoenix, Arizona 85050; Southwest Research and Resource Center, Phoenix, Arizona 85006; Rossignol Medical Center, Phoenix Arizona 85050.
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Mohammadi NA, Ahring PK, Yu Liao VW, Chua HC, Ortiz de la Rosa S, Johannesen KM, Michaeli-Yossef Y, Vincent-Devulder A, Meridda C, Bruel AL, Rossi A, Patel C, Klepper J, Bonanni P, Minghetti S, Trivisano M, Specchio N, Amor D, Auvin S, Baer S, Meyer P, Milh M, Salpietro V, Maroofian R, Lemke JR, Weckhuysen S, Christophersen P, Rubboli G, Chebib M, Jensen AA, Absalom NL, Møller RS. Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants. EBioMedicine 2024; 106:105236. [PMID: 38996765 PMCID: PMC11296288 DOI: 10.1016/j.ebiom.2024.105236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/23/2024] [Accepted: 06/26/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. METHODS Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. FINDINGS Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. INTERPRETATION The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. FUNDING This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.
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Affiliation(s)
- Nazanin Azarinejad Mohammadi
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Philip Kiær Ahring
- School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Vivian Wan Yu Liao
- School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Han Chow Chua
- Sydney Pharmacy School, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Sebastián Ortiz de la Rosa
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Katrine Marie Johannesen
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Yael Michaeli-Yossef
- Pediatric Neurology Unit and Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel
| | | | | | | | - Alessandra Rossi
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Pediatric Clinic, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Chirag Patel
- Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD 4029, Australia
| | - Joerg Klepper
- Children's Hospital Aschaffenburg-Alzenau, Aschaffenburg, Germany
| | - Paolo Bonanni
- IRCCS E. Medea Scientific Institute, Epilepsy Unit, Conegliano, Treviso, Italy
| | - Sara Minghetti
- IRCCS E. Medea Scientific Institute, Clinical Neurophysiology Unit, Bosisio Parini, LC, Italy
| | - Marina Trivisano
- Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
| | - Nicola Specchio
- Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy
| | - David Amor
- Murdoch Children's Research Institute, Melbourne, Australia
| | - Stéphane Auvin
- Université de Paris, Child Neurology & Epilepsy, Paris, France; Robert-Debré Hospital, Center for Rare Epilepsies - Pediatric Neurology, Paris, France
| | - Sarah Baer
- Department of Paediatric Neurology, French Reference Center of Rare Epilepsies CREER, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Pierre Meyer
- Paediatric Neurology Department, Phymedexp, Montpellier University, Inserm, CNRS, University Hospital Montpellier, Montpellier, France
| | - Mathieu Milh
- Department of Pediatric Neurology, AP-HM, La Timone Children's Hospital, Marseille, France; Faculté de Médecine Timone, Aix Marseille Univ, INSERM, MMG, U1251, ERN EpiCARE, Marseille, France
| | - Vincenzo Salpietro
- Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, Genoa, Italy
| | - Reza Maroofian
- Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK
| | - Johannes R Lemke
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
| | - Sarah Weckhuysen
- Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium
| | | | - Guido Rubboli
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mary Chebib
- School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia
| | - Anders A Jensen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nathan L Absalom
- School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; School of Science, Western Sydney University, Sydney, Australia.
| | - Rikke Steensbjerre Møller
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
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André T, van Berkel AA, Singh G, Abualrous ET, Diwan GD, Schmenger T, Braun L, Malsam J, Toonen RF, Freund C, Russell RB, Verhage M, Söllner TH. Reduced Protein Stability of 11 Pathogenic Missense STXBP1/MUNC18-1 Variants and Improved Disease Prediction. Biol Psychiatry 2024; 96:125-136. [PMID: 38490366 DOI: 10.1016/j.biopsych.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Pathogenic variants in STXBP1/MUNC18-1 cause severe encephalopathies that are among the most common in genetic neurodevelopmental disorders. Different molecular disease mechanisms have been proposed, and pathogenicity prediction is limited. In this study, we aimed to define a generalized disease concept for STXBP1-related disorders and improve prediction. METHODS A cohort of 11 disease-associated and 5 neutral variants (detected in healthy individuals) were tested in 3 cell-free assays and in heterologous cells and primary neurons. Protein aggregation was tested using gel filtration and Triton X-100 insolubility. PRESR (predicting STXBP1-related disorder), a machine learning algorithm that uses both sequence- and 3-dimensional structure-based features, was developed to improve pathogenicity prediction using 231 known disease-associated variants and comparison to our experimental data. RESULTS Disease-associated variants, but none of the neutral variants, produced reduced protein levels. Cell-free assays demonstrated directly that disease-associated variants have reduced thermostability, with most variants denaturing around body temperature. In addition, most disease-associated variants impaired SNARE-mediated membrane fusion in a reconstituted assay. Aggregation/insolubility was observed for none of the variants in vitro or in neurons. PRESR outperformed existing tools substantially: Matthews correlation coefficient = 0.71 versus <0.55. CONCLUSIONS These data establish intrinsic protein instability as the generalizable, primary cause for STXBP1-related disorders and show that protein-specific ortholog and 3-dimensional information improve disease prediction. PRESR is a publicly available diagnostic tool.
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Affiliation(s)
- Timon André
- Heidelberg University Biochemistry Centre, Heidelberg, Germany
| | - Annemiek A van Berkel
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, the Netherlands; Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNRC), University Medical Center Amsterdam; Amsterdam 1081 HV, the Netherlands
| | - Gurdeep Singh
- Heidelberg University Biochemistry Centre, Heidelberg, Germany; BioQuant, Heidelberg University, Heidelberg, Germany
| | - Esam T Abualrous
- Laboratory of Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany; Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Gaurav D Diwan
- Heidelberg University Biochemistry Centre, Heidelberg, Germany; BioQuant, Heidelberg University, Heidelberg, Germany
| | - Torsten Schmenger
- Heidelberg University Biochemistry Centre, Heidelberg, Germany; BioQuant, Heidelberg University, Heidelberg, Germany
| | - Lara Braun
- Heidelberg University Biochemistry Centre, Heidelberg, Germany
| | - Jörg Malsam
- Heidelberg University Biochemistry Centre, Heidelberg, Germany
| | - Ruud F Toonen
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, the Netherlands
| | - Christian Freund
- Laboratory of Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Robert B Russell
- Heidelberg University Biochemistry Centre, Heidelberg, Germany; BioQuant, Heidelberg University, Heidelberg, Germany
| | - Matthijs Verhage
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, the Netherlands; Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNRC), University Medical Center Amsterdam; Amsterdam 1081 HV, the Netherlands.
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van der Westhuizen ET. Single nucleotide variations encoding missense mutations in G protein-coupled receptors may contribute to autism. Br J Pharmacol 2024; 181:2158-2181. [PMID: 36787962 DOI: 10.1111/bph.16057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/21/2022] [Accepted: 02/04/2023] [Indexed: 02/16/2023] Open
Abstract
Autism is a neurodevelopmental condition with a range of symptoms that vary in intensity and severity from person to person. Genetic sequencing has identified thousands of genes containing mutations in autistic individuals, which may contribute to the development of autistic symptoms. Several of these genes encode G protein-coupled receptors (GPCRs), which are cell surface expressed proteins that transduce extracellular messages to the intracellular space. Mutations in GPCRs can impact their function, resulting in aberrant signalling within cells and across neurotransmitter systems in the brain. This review summarises the current knowledge on autism-associated single nucleotide variations encoding missense mutations in GPCRs and the impact of these genetic mutations on GPCR function. For some autism-associated mutations, changes in GPCR expression levels, ligand affinity, potency and efficacy have been observed. However, for many the functional consequences remain unknown. Thus, further work to characterise the functional impacts of the genetically identified mutations is required. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Frye RE, Rincon N, McCarty PJ, Brister D, Scheck AC, Rossignol DA. Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis. Neurobiol Dis 2024; 197:106520. [PMID: 38703861 DOI: 10.1016/j.nbd.2024.106520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
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Affiliation(s)
- Richard E Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Southwest Autism Research and Resource Center, Phoenix, AZ, USA; Rossignol Medical Center, Phoenix, AZ, USA.
| | | | - Patrick J McCarty
- Tulane University School of Medicine, New Orleans, LA 70113, United States of America.
| | | | - Adrienne C Scheck
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, United States of America.
| | - Daniel A Rossignol
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Rossignol Medical Center, Aliso Viejo, CA, USA
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Fellner A, Wali GM, Mahant N, Grosz BR, Ellis M, Narayanan RK, Ng K, Davis RL, Tchan MC, Kotschet K, Yeow D, Rudaks LI, Siow SF, Wali G, Yiannikas C, Hobbs M, Copty J, Geaghan M, Darveniza P, Liang C, Williams LJ, Chang FCF, Morales-Briceño H, Tisch S, Hayes M, Whyte S, Kummerfeld S, Kennerson ML, Cowley MJ, Fung VSC, Sue CM, Kumar KR. Genome sequencing reanalysis increases the diagnostic yield in dystonia. Parkinsonism Relat Disord 2024; 124:107010. [PMID: 38772265 DOI: 10.1016/j.parkreldis.2024.107010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/15/2024] [Accepted: 05/12/2024] [Indexed: 05/23/2024]
Abstract
PURPOSE We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.
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Affiliation(s)
- Avi Fellner
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Neurogenetics Clinic, Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
| | | | - Neil Mahant
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia
| | - Bianca R Grosz
- Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia
| | - Melina Ellis
- Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia
| | - Ramesh K Narayanan
- Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia
| | - Karl Ng
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia
| | - Ryan L Davis
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia
| | - Michel C Tchan
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia
| | - Katya Kotschet
- Clinical Neurosciences, St. Vincent's Hospital, Melbourne, Australia
| | - Dennis Yeow
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia
| | - Laura I Rudaks
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia
| | - Sue-Faye Siow
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia
| | - Gautam Wali
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia
| | - Con Yiannikas
- Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - Matthew Hobbs
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Joseph Copty
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Michael Geaghan
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Paul Darveniza
- Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Christina Liang
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia
| | - Laura J Williams
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia
| | - Florence C F Chang
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Hugo Morales-Briceño
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Stephen Tisch
- Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | - Michael Hayes
- Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - Scott Whyte
- Department of Neurology, Gosford Hospital, Gosford, Australia
| | - Sarah Kummerfeld
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Marina L Kennerson
- Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia
| | - Mark J Cowley
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; Children's Cancer Institute, University of New South Wales, Sydney, Australia
| | - Victor S C Fung
- Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Carolyn M Sue
- Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | - Kishore R Kumar
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
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Pagnamenta AT, Yu J, Walker S, Noble AJ, Lord J, Dutta P, Hashim M, Camps C, Green H, Devaiah S, Nashef L, Parr J, Fratter C, Ibnouf Hussein R, Lindsay SJ, Lalloo F, Banos-Pinero B, Evans D, Mallin L, Waite A, Evans J, Newman A, Allen Z, Perez-Becerril C, Ryan G, Hart R, Taylor J, Bedenham T, Clement E, Blair E, Hay E, Forzano F, Higgs J, Canham N, Majumdar A, McEntagart M, Lahiri N, Stewart H, Smithson S, Calpena E, Jackson A, Banka S, Titheradge H, McGowan R, Rankin J, Shaw-Smith C, Evans DG, Burghel GJ, Smith MJ, Anderson E, Madhu R, Firth H, Ellard S, Brennan P, Anderson C, Taupin D, Rogers MT, Cook JA, Durkie M, East JE, Fowler D, Wilson L, Igbokwe R, Gardham A, Tomlinson I, Baralle D, Uhlig HH, Taylor JC. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project. Am J Hum Genet 2024; 111:1140-1164. [PMID: 38776926 PMCID: PMC11179413 DOI: 10.1016/j.ajhg.2024.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.
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Affiliation(s)
- Alistair T Pagnamenta
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
| | - Jing Yu
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK; Novo Nordisk Oxford Research Centre, Oxford, UK
| | | | - Alexandra J Noble
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Jenny Lord
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK
| | - Prasun Dutta
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Mona Hashim
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Carme Camps
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Hannah Green
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Smrithi Devaiah
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Lina Nashef
- Department of Neurology, King's College Hospital, London, UK
| | - Jason Parr
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Carl Fratter
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rana Ibnouf Hussein
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Sarah J Lindsay
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Fiona Lalloo
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Benito Banos-Pinero
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - David Evans
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Lucy Mallin
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Adrian Waite
- Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, UK
| | - Julie Evans
- Bristol Genetics Laboratory, North Bristol NHS Trust, Bristol, UK
| | - Andrew Newman
- The All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK
| | - Zoe Allen
- North Thames Rare and Inherited Disease Laboratory, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Cristina Perez-Becerril
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Gavin Ryan
- West Midlands Regional Genetics Laboratory, Central and South Genomic Laboratory Hub, Birmingham, UK
| | - Rachel Hart
- Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK
| | - John Taylor
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Tina Bedenham
- Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Emma Clement
- North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ed Blair
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Eleanor Hay
- North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Francesca Forzano
- Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Jenny Higgs
- Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK
| | - Natalie Canham
- Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK
| | - Anirban Majumdar
- Department of Paediatric Neurology, Bristol Children's Hospital, Bristol, UK
| | - Meriel McEntagart
- SW Thames Centre for Genomic Medicine, University of London & St George's University Hospitals NHS Foundation Trust, St George's, London, UK
| | - Nayana Lahiri
- SW Thames Centre for Genomic Medicine, University of London & St George's University Hospitals NHS Foundation Trust, St George's, London, UK
| | - Helen Stewart
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Sarah Smithson
- Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Eduardo Calpena
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; Grupo de Investigación en Biomedicina Molecular, Celular y Genómica, Unidad CIBERER (CB06/07/1030), Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Adam Jackson
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Siddharth Banka
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Hannah Titheradge
- Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Ruth McGowan
- West of Scotland Centre for Genomic Medicine, Glasgow, UK
| | - Julia Rankin
- Department of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, UK
| | - Charles Shaw-Smith
- Department of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, UK
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - George J Burghel
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Miriam J Smith
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
| | - Emily Anderson
- Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK
| | - Rajesh Madhu
- Paediatric Neurosciences Department, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Helen Firth
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Sian Ellard
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Paul Brennan
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle University, Newcastle, UK
| | - Claire Anderson
- Canberra Clinical Genomics, Canberra Health Services and The Australian National University, Canberra, ACT, Australia
| | - Doug Taupin
- Cancer Research, Canberra Hospital, Canberra, ACT, Australia
| | - Mark T Rogers
- The All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, UK
| | - Jackie A Cook
- Department of Clinical Genetics, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Miranda Durkie
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, North East and Yorkshire Genomic Laboratory Hub, Sheffield, UK
| | - James E East
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Darren Fowler
- Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Louise Wilson
- North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Rebecca Igbokwe
- Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Alice Gardham
- North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ian Tomlinson
- Department of Oncology, University of Oxford, Oxford, UK
| | - Diana Baralle
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Holm H Uhlig
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Jenny C Taylor
- Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
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Abela L, Gianfrancesco L, Tagliatti E, Rossignoli G, Barwick K, Zourray C, Reid KM, Budinger D, Ng J, Counsell J, Simpson A, Pearson TS, Edvardson S, Elpeleg O, Brodsky FM, Lignani G, Barral S, Kurian MA. Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy. Brain 2024; 147:2023-2037. [PMID: 38242634 PMCID: PMC11146427 DOI: 10.1093/brain/awae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/10/2023] [Accepted: 12/16/2023] [Indexed: 01/21/2024] Open
Abstract
DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harbouring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. To explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
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Affiliation(s)
- Lucia Abela
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Lorita Gianfrancesco
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Erica Tagliatti
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
- Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, 20089 Milano, Italy
| | - Giada Rossignoli
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Katy Barwick
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Clara Zourray
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Kimberley M Reid
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Dimitri Budinger
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Joanne Ng
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
- Genetic Therapy Accelerator Centre, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
| | - John Counsell
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Arlo Simpson
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Toni S Pearson
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032-3784, USA
- Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University, Columbus, OH 43210, USA
- Department of Neurology, Nationwide Children’s Hospital, Ohio State University, Columbus, OH 43210, USA
| | - Simon Edvardson
- Department of Genetics, Hadassah, Hebrew University Medical Center, 9574869 Jerusalem, Israel
| | - Orly Elpeleg
- Department of Genetics, Hadassah, Hebrew University Medical Center, 9574869 Jerusalem, Israel
| | - Frances M Brodsky
- Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, UK
| | - Gabriele Lignani
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Serena Barral
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
| | - Manju A Kurian
- Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, WC1N 1DZ, UK
- Department of Neurology, Great Ormond Street Hospital, London, WC1N 3JH, UK
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de Masfrand S, Cogné B, Nizon M, Deb W, Goldenberg A, Lecoquierre F, Nicolas G, Bournez M, Vitobello A, Mau-Them FT, le Guyader G, Bilan F, Bauer P, Zweier C, Piard J, Pasquier L, Bézieau S, Gerard B, Faivre L, Saugier-Veber P, Piton A, Isidor B. Penetrance, variable expressivity and monogenic neurodevelopmental disorders. Eur J Med Genet 2024; 69:104932. [PMID: 38453051 DOI: 10.1016/j.ejmg.2024.104932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 03/01/2024] [Accepted: 03/02/2024] [Indexed: 03/09/2024]
Abstract
PURPOSE Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance. METHOD From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study. RESULTS We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent. CONCLUSION Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.
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Affiliation(s)
- Servane de Masfrand
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France.
| | - Benjamin Cogné
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France
| | - Mathilde Nizon
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France
| | - Wallid Deb
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France
| | - Alice Goldenberg
- CHU Rouen, Service de Génétique et Centre de Référence pour Les Troubles Du Développement, 76183, Rouen, France
| | - François Lecoquierre
- CHU Rouen, Service de Génétique et Centre de Référence pour Les Troubles Du Développement, 76183, Rouen, France
| | - Gaël Nicolas
- CHU Rouen, Service de Génétique et Centre de Référence pour Les Troubles Du Développement, 76183, Rouen, France
| | - Marie Bournez
- Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France
| | - Antonio Vitobello
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, Dijon, France; Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France
| | - Frédéric Tran Mau-Them
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, Dijon, France; Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France
| | - Gwenaël le Guyader
- Service de Génétique Clinique, Centre de Compétence Maladies Rares Anomalies Du Développement, CHU de Poitiers, Poitiers, France
| | - Frédéric Bilan
- Service de Génétique Clinique, Centre de Compétence Maladies Rares Anomalies Du Développement, CHU de Poitiers, Poitiers, France
| | | | | | - Juliette Piard
- Centre de Génétique Humaine and Integrative and Cognitive Neuroscience Research Unit EA481, Université de Franche-Comté, Besançon, France
| | | | - Stéphane Bézieau
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France
| | - Bénédicte Gerard
- Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Laurence Faivre
- Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France; Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France
| | - Pascale Saugier-Veber
- CHU Rouen, Service de Génétique et Centre de Référence pour Les Troubles Du Développement, 76183, Rouen, France
| | - Amélie Piton
- Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Bertrand Isidor
- Nantes Université, CHU Nantes, Service de Génétique Médicale, 44000, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, 44000 Nantes, France.
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Rouzier C, Pion E, Chaussenot A, Bris C, Ait‐El‐Mkadem Saadi S, Desquiret‐Dumas V, Gueguen N, Fragaki K, Amati‐Bonneau P, Barcia G, Gaignard P, Steffann J, Pennisi A, Bonnefont J, Lebigot E, Bannwarth S, Francou B, Rucheton B, Sternberg D, Martin‐Negrier M, Trimouille A, Hardy G, Allouche S, Acquaviva‐Bourdain C, Pagan C, Lebre A, Reynier P, Cossee M, Attarian S, Paquis‐Flucklinger V, Procaccio V. Primary mitochondrial disorders and mimics: Insights from a large French cohort. Ann Clin Transl Neurol 2024; 11:1478-1491. [PMID: 38703036 PMCID: PMC11187946 DOI: 10.1002/acn3.52062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 03/23/2024] [Indexed: 05/06/2024] Open
Abstract
OBJECTIVE The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes. METHODS Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes. RESULTS The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases. INTERPRETATION We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.
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Affiliation(s)
- Cécile Rouzier
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | - Emmanuelle Pion
- Filnemus, laboratoire de génétique moléculaire, CHUMontpellierFrance
| | - Annabelle Chaussenot
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | - Céline Bris
- Service de génétique, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
| | - Samira Ait‐El‐Mkadem Saadi
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | - Valérie Desquiret‐Dumas
- Service de biochimie et biologie moléculaire, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
| | - Naïg Gueguen
- Service de biochimie et biologie moléculaire, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
| | - Konstantina Fragaki
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | - Patrizia Amati‐Bonneau
- Service de biochimie et biologie moléculaire, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
| | - Giulia Barcia
- Service de médecine génomique des maladies rares, Hôpital Necker‐Enfants MaladesUniversité Paris Cité, Institut Imagine Unité UMR 1161ParisFrance
| | - Pauline Gaignard
- Service de Biochimie, GHU APHP Paris SaclayHôpital BicêtreLe Kremlin‐BicêtreFrance
| | - Julie Steffann
- Service de médecine génomique des maladies rares, Hôpital Necker‐Enfants MaladesUniversité Paris Cité, Institut Imagine Unité UMR 1161ParisFrance
| | - Alessandra Pennisi
- Service de médecine génomique des maladies rares, Hôpital Necker‐Enfants MaladesUniversité Paris Cité, Institut Imagine Unité UMR 1161ParisFrance
| | - Jean‐Paul Bonnefont
- Service de médecine génomique des maladies rares, Hôpital Necker‐Enfants MaladesUniversité Paris Cité, Institut Imagine Unité UMR 1161ParisFrance
| | - Elise Lebigot
- Service de Biochimie, GHU APHP Paris SaclayHôpital BicêtreLe Kremlin‐BicêtreFrance
| | - Sylvie Bannwarth
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | - Bruno Francou
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | | | - Damien Sternberg
- Unité Fonctionnelle de cardiogénétique et myogénétique moléculaire et cellulaire, Centre de génétique moléculaire et chromosomiqueAP‐HP Sorbonne Université, Hopital de la Pitié‐SalpêtrièreParisFrance
| | - Marie‐Laure Martin‐Negrier
- Unité fonctionnelle d'histologie moléculaire, Service de pathologieCHU Bordeaux‐GU PellegrinBordeauxFrance
| | - Aurélien Trimouille
- Unité fonctionnelle d'histologie moléculaire, Service de pathologieCHU Bordeaux‐GU PellegrinBordeauxFrance
| | - Gaëlle Hardy
- Laboratoire de Génétique Moléculaire: Maladies Héréditaires et OncologieInstitut de Biologie et de Pathologie, CHU Grenoble AlpesGrenobleFrance
| | - Stéphane Allouche
- Service de biochimieInstitut Territorial de Biologie en Santé, CHU Caen, Hôpital de la Côte de NacreCaenFrance
| | - Cécile Acquaviva‐Bourdain
- Service de biochimie et biologie moléculaire Grand Est, UM Maladies Héréditaires du Métabolisme, Centre de biologie et pathologie EstCHU Lyon HCL, GH EstLyonFrance
| | - Cécile Pagan
- Service de biochimie et biologie moléculaire Grand Est, UM Maladies Héréditaires du Métabolisme, Centre de biologie et pathologie EstCHU Lyon HCL, GH EstLyonFrance
| | - Anne‐Sophie Lebre
- Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266 [Krebs team]Université de Reims Champagne‐Ardenne (UFR médicale) ‐ CHU de Reims‐Université Paris CitéParisFrance
| | - Pascal Reynier
- Service de biochimie et biologie moléculaire, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
| | - Mireille Cossee
- Laboratoire de Génétique Moléculaire, CHU Montpellier, PhyMedExpUniversité de Montpellier, INSERM, CNRSMontpellierFrance
| | - Shahram Attarian
- Service des Maladies Neuromusculaires et la SLA, FILNEMUS, Euro‐NMDAIX‐CHU La TimoneMarseille UniversitéMarseilleFrance
| | - Véronique Paquis‐Flucklinger
- Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU NiceUniversité Côte d'Azur, CNRS, INSERM, IRCANNiceFrance
| | | | - Vincent Procaccio
- Service de génétique, Institut de Biologie en santé, CHU AngersUniv Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFR ICATAngersFrance
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Usnich T, Becker LF, Nagel I, Bäumer T, Münchau A. Partially Levodopa-Responsive Parkinsonism in a Carrier of a Novel Pathogenic CLTC Variant. Mov Disord Clin Pract 2024; 11:749-750. [PMID: 38586890 PMCID: PMC11145102 DOI: 10.1002/mdc3.14037] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 04/09/2024] Open
Affiliation(s)
- Tatiana Usnich
- Institute of Neurogenetics, University of LübeckLübeckGermany
| | - Leonie F. Becker
- Institute of Systems Motor Science, CBBM, University of LübeckLübeckGermany
- Department of PediatricsUniversity Hospital Medical Center Schleswig‐HolsteinLübeckGermany
| | - Inga Nagel
- Institute of Human Genetics, University of LübeckLübeckGermany
| | - Tobias Bäumer
- Institute of Systems Motor Science, CBBM, University of LübeckLübeckGermany
| | - Alexander Münchau
- Institute of Systems Motor Science, CBBM, University of LübeckLübeckGermany
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Roelens R, Peigneur ANF, Voets T, Vriens J. Neurodevelopmental disorders caused by variants in TRPM3. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119709. [PMID: 38522727 DOI: 10.1016/j.bbamcr.2024.119709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 03/26/2024]
Abstract
Developmental and epileptic encephalopathies (DEE) are a broad and varied group of disorders that affect the brain and are characterized by epilepsy and comorbid intellectual disability (ID). These conditions have a broad spectrum of symptoms and can be caused by various underlying factors, including genetic mutations, infections, and other medical conditions. The exact cause of DEE remains largely unknown in the majority of cases. However, in around 25 % of patients, rare nonsynonymous coding variants in genes encoding ion channels, cell-surface receptors, and other neuronally expressed proteins are identified. This review focuses on a subgroup of DEE patients carrying variations in the gene encoding the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel, where recent data indicate that gain-of-function of TRPM3 channel activity underlies a spectrum of dominant neurodevelopmental disorders.
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Affiliation(s)
- Robbe Roelens
- Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Molecular Medicine, KU Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
| | - Ana Nogueira Freitas Peigneur
- Laboratory of Ion Channel Research, Department of Molecular Medicine, KU Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
| | - Thomas Voets
- Laboratory of Ion Channel Research, Department of Molecular Medicine, KU Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
| | - Joris Vriens
- Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Molecular Medicine, KU Leuven, Leuven, Belgium.
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Ren Y, Luo X, Tong H, Wang S, Yan J, Lin L, Chen Y. Preliminary Study on Clinical Characteristics and Pathogenesis of IQSEC2 Mutations Patients. Pharmgenomics Pers Med 2024; 17:289-318. [PMID: 38827181 PMCID: PMC11144418 DOI: 10.2147/pgpm.s455840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/18/2024] [Indexed: 06/04/2024] Open
Abstract
Background The IQ motif and Sec7 domain ArfGEF 2 (IQSEC2), an X-linked gene that encodes the BRAG1 protein, is a guanine nucleotide exchange factor for the ADP ribosylation factor (ARF) protein family in the small guanosine triphosphate (GTP) binding protein. Mutations in this gene result in disorders such as intellectual disability (ID) and epilepsy. In this study, we analyze the clinical features of two patients with IQSEC2-mutation-related disease and discuss their possible pathogenesis. Methods The two patients were diagnosed with ID and epilepsy. Genetic testing was performed using whole-exome sequencing, and the three-dimensional protein structure was analyzed. UCSC Genome Browser was used to analyze the conservation of IQSEC2 in different species. We compared IQSEC2 expression in the proband families with that in a control group, as well as the expression of the postsynaptic identity protein 95 (PSD-95), synapse-associated protein 97 (SAP97), ADP ribosylation factor 6 (ARF-6), and insulin receptor substrate 53kDa (IRSP53) genes interacting with IQSEC2. Results We identified two semi-zygote mutations located in conserved positions in different species: an unreported de novo mutation, C.3576C>A (p. Tyr1192*), and a known mutation, c.2983C>T (p. Arg995Trp). IQSEC2 mutations resulted in significant changes in the predicted three-dimensional protein structure, while its expression in the two probands was significantly lower than that in the age-matched control group, and IQSEC2 expression in proband 1 was lower than that in his family members. The expression levels of PSD-95, ARF-6, and SAP97, IRSP 53, which interact with IQSEC2, were also significantly different from those in the family members and age-matched healthy children. Conclusion The clinical phenotype resulting from IQSEC2 mutations can be explained by the significant decrease in its expression, loss of function of the mutant protein, and change in the expression of related genes. Our results provide novel insights into the molecular phenotype conferred by the IQSEC2 variants.
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Affiliation(s)
- Yun Ren
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Xiaona Luo
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Haiyan Tong
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Simei Wang
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Jinbin Yan
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Longlong Lin
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
| | - Yucai Chen
- Department of Neurology, Shanghai Children’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, People’s Republic of China
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Li R, Yang J, Ma J, Zhang A, Li H. Case report: Novel NUS1 variant in a Chinese patient with tremors and intellectual disability. Front Genet 2024; 15:1373448. [PMID: 38655050 PMCID: PMC11035736 DOI: 10.3389/fgene.2024.1373448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction Nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) gene variants are associated with a range of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorders of glycosylation. Additionally, cases describing genotypes and clinical features are rare. Case Presentation Herein, we report the case of a 23-year-old Chinese female patient who presented with tremors, intellectual disability, and epilepsy. A history of carbon monoxide exposure, brain trauma, or encephalitis was not present in this case. Trio whole-exome sequencing analysis revealed a de novo pathogenic variant of c.750del in exon 4, leading to p.Leu251* amino acid substitution. Genetic analysis failed to identify the identical mutations in the remaining family members who underwent screening. The patient was diagnosed with a rare congenital disease, "congenital glycosylation disorder, type 1aa, autosomal dominant, type 55, with seizures (MRD-55)." Conclusion We provide further evidence for the role of variants in NUS1 in the development of tremors, epilepsy, and intellectual disabilities. These findings expand our understanding of the clinical phenotypes of NUS1 variants.
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Affiliation(s)
- Ruolin Li
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Jiayi Yang
- Clinical Medical College, Jining Medical University, Jining, China
| | - Jinfeng Ma
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Aimei Zhang
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Hongfang Li
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
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AlSabah AA, Alsalmi M, Massie R, Bilodeau MC, Campeau PM, McGraw S, D'Agostino MD. An adult patient with Tatton-Brown-Rahman syndrome caused by a novel DNMT3A variant and axonal polyneuropathy. Am J Med Genet A 2024; 194:e63484. [PMID: 38041495 DOI: 10.1002/ajmg.a.63484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 11/07/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023]
Abstract
Tatton-Brown-Rahman syndrome (TBRS) is a rare autosomal dominant overgrowth syndrome first reported in 2014 and caused by pathogenic variants in the DNA methyltransferase 3A (DNMT3A) gene. All individuals reported to date share a phenotype of somatic overgrowth, dysmorphic features, and intellectual disability. Peripheral neuropathy was not described in these cases. We report an adult patient with TBRS caused by a novel pathogenic DNMT3A variant (NM_175629.2: c.2036G>A, p.(Arg688His)) harboring an axonal length-dependent sensory-motor polyneuropathy. Extensive laboratory and molecular genetic work-up failed to identify alternative causes for this patient's neuropathy. We propose that axonal neuropathy may be a novel, age-dependent phenotypic feature in adults with TBRS and suggest that this syndrome should be considered in the differential diagnosis of patients with overgrowth, cognitive and psychiatric difficulties, and peripheral neuropathy.
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Affiliation(s)
- Al-Alya AlSabah
- Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
| | - Mohammed Alsalmi
- Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
| | - Rami Massie
- Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
| | - Marie-Claude Bilodeau
- Clinique de Psychiatrie, Santé Mentale et Dépendances, CIUSSS MCQ, Hôpital Sainte-Croix, Drummondville, Quebec, Canada
| | - Philippe M Campeau
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
| | - Serge McGraw
- Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Department of Obstetrics and Gynecology, Université de Montreal, Montreal, Quebec, Canada
| | - Maria Daniela D'Agostino
- Division of Medical Genetics, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada
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