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Jeridi C, Rachdi A, Nabli F, Saied Z, Zouari R, Ben Mohamed D, Ben Said M, Masmoudi S, Ben Sassi S, Amouri R. Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes. J Neurogenet 2023; 37:124-130. [PMID: 38109176 DOI: 10.1080/01677063.2023.2281916] [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: 02/07/2023] [Accepted: 11/03/2023] [Indexed: 12/19/2023]
Abstract
Autosomal recessive cerebellar ataxias (ARCA) constitute a highly heterogeneous group of progressive neurodegenerative disorders that typically occur prior to adulthood. Despite some clinical resemblance between these disorders, different genes are involved. We report in this study four Tunisian patients belonging to the same large consanguineous family, sharing autosomal recessive cerebellar ataxia phenotypes but with clinical, biological, electrophysiological, and radiological differences leading to the diagnosis of two distinct ARCA caused by two distinct gene defects. Two of our patients presented ataxia with the vitamin E deficiency (AVED) phenotype, and the other two presented ataxia with oculo-motor apraxia 2 (AOA2). Genetic testing confirmed the clinical diagnosis by the detection of a frameshift c.744delA pathogenic variant in the TTPA gene, which is the most frequent in Tunisia, and a new variant c.1075dupT in the SETX gene. In Tunisia, data suggest that genetic disorders are common. The combined effects of the founder effect and inbreeding, added to genetic drift, may increase the frequency of detrimental rare disorders. The genetic heterogeneity observed in this family highlights the difficulty of genetic counseling in an inbred population. The examination and genetic testing of all affected patients, not just the index patient, is essential to not miss a treatable ataxia such as AVED, as in the case of this family.
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Affiliation(s)
- Cyrine Jeridi
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Amine Rachdi
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Fatma Nabli
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Zacharia Saied
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Rania Zouari
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Dina Ben Mohamed
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Mariem Ben Said
- Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia
| | - Saber Masmoudi
- Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisia
| | - Samia Ben Sassi
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
| | - Rim Amouri
- Molecular Neurobiology and Neuropathology Department, National Institute Mongi Ben Hamida of Neurology, Tunisia
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Dragašević-Mišković N, Stanković I, Milovanović A, Kostić VS. Autosomal recessive adult onset ataxia. J Neurol 2021; 269:504-533. [PMID: 34499204 DOI: 10.1007/s00415-021-10763-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 11/24/2022]
Abstract
Autosomal recessive ataxias (ARCA) represent a complex group of diseases ranging from primary ataxias to rare and complex metabolic disorders in which ataxia is a part of the clinical picture. Small number of ARCA manifest exclusively in adulthood, while majority of typical childhood onset ARCA may also start later with atypical clinical presentation. We have systematically searched the literature for ARCA with adult onset, both in the group of primary ataxias including those that are less frequently described in isolated or in a small number of families, and also in the group of complex and metabolic diseases in which ataxia is only part of the clinical picture. We propose an algorithm that could be used when encountering a patient with adult onset sporadic or recessive ataxia in whom the acquired causes are excluded. ARCA are frequently neglected in the differential diagnosis of adult-onset ataxias. Rising awareness of their clinical significance is important, not only because some of these disorders may be potentially treatable, but also for prognostic implications and inclusion of patients to future clinical trials with disease modifying agents.
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Affiliation(s)
- Nataša Dragašević-Mišković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia.
| | - Iva Stanković
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Andona Milovanović
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
| | - Vladimir S Kostić
- Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotića 6, 11000, Belgrade, Serbia
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Akinyemi RO, Owolabi MO, Oyeniyi T, Ovbiagele B, Arnett DK, Tiwari HK, Walker R, Ogunniyi A, Kalaria RN. Neurogenomics in Africa: Perspectives, progress, possibilities and priorities. J Neurol Sci 2016; 366:213-223. [PMID: 27288810 DOI: 10.1016/j.jns.2016.05.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 05/04/2016] [Indexed: 11/18/2022]
Abstract
The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.
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Affiliation(s)
- Rufus O Akinyemi
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Nigeria; Institute of Neuroscience, Newcastle University, UK.
| | - Mayowa O Owolabi
- Department of Medicine, College of Medicine, University of Ibadan, Nigeria
| | | | - Bruce Ovbiagele
- Department of Neurosciences, Medical University of South Carolina, USA
| | - Donna K Arnett
- School of Public Health, University of Alabama at Birmingham, USA
| | - Hemant K Tiwari
- School of Public Health, University of Alabama at Birmingham, USA
| | - Richard Walker
- Institute of Health and Society, Newcastle University, UK
| | - Adesola Ogunniyi
- Department of Medicine, College of Medicine, University of Ibadan, Nigeria
| | - Raj N Kalaria
- Institute of Neuroscience, Newcastle University, UK.
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Mancini C, Orsi L, Guo Y, Li J, Chen Y, Wang F, Tian L, Liu X, Zhang J, Jiang H, Nmezi BS, Tatsuta T, Giorgio E, Di Gregorio E, Cavalieri S, Pozzi E, Mortara P, Caglio MM, Balducci A, Pinessi L, Langer T, Padiath QS, Hakonarson H, Zhang X, Brusco A. An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2. BMC MEDICAL GENETICS 2015; 16:16. [PMID: 25927548 PMCID: PMC4422141 DOI: 10.1186/s12881-015-0159-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 02/26/2015] [Indexed: 11/10/2022]
Abstract
BACKGROUND Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases. METHODS We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene. RESULTS Exome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function. CONCLUSIONS Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant). We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.
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Affiliation(s)
- Cecilia Mancini
- Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy.
| | - Laura Orsi
- Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
| | - Yiran Guo
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
| | | | | | - Fengxiang Wang
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
| | - Lifeng Tian
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
| | | | | | - Hui Jiang
- BGI-Shenzhen, Shenzhen, 510803, China. .,Shenzhen Key Laboratory of Genomics, Shenzhen, 518083, China. .,The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, 510803, China.
| | - Bruce Shike Nmezi
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
| | - Takashi Tatsuta
- Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50931, Germany.
| | - Elisa Giorgio
- Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy.
| | - Eleonora Di Gregorio
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
| | - Simona Cavalieri
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
| | - Elisa Pozzi
- Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy.
| | - Paolo Mortara
- Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. .,Department of Neuroscience, University of Torino, Torino, 10126, Italy.
| | - Maria Marcella Caglio
- Department of Neuroscience, University of Torino, Torino, 10126, Italy. .,Division of Neurology III, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
| | - Alessandro Balducci
- Department of Neuroscience, University of Torino, Torino, 10126, Italy. .,Division of Neurology III, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
| | - Lorenzo Pinessi
- Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. .,Department of Neuroscience, University of Torino, Torino, 10126, Italy.
| | - Thomas Langer
- Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50931, Germany. .,Max-Planck-Institute for Biology of Aging, Cologne, 50931, Germany.
| | - Quasar S Padiath
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. .,Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. .,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Xiuqing Zhang
- BGI-Shenzhen, Shenzhen, 510803, China. .,Shenzhen Key Laboratory of Genomics, Shenzhen, 518083, China. .,The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, 510803, China.
| | - Alfredo Brusco
- Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy. .,Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy.
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El Euch-Fayache G, Bouhlal Y, Amouri R, Feki M, Hentati F. Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency. ACTA ACUST UNITED AC 2013; 137:402-10. [PMID: 24369383 DOI: 10.1093/brain/awt339] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.
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Affiliation(s)
- Ghada El Euch-Fayache
- 1 Department of Neurology, Mongi Ben Hamida National Institute of Neurology, La Rabta, Tunis 1007, Tunisia
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