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Tao C, Zhao M, Zhang X, Hao J, Huo Q, Sun J, Xing J, Zhang Y, Zhao J, Huang H. Novel compound heterozygous mutations of the NPC1 gene associated with Niemann-pick disease type C: a case report and review of the literature. BMC Infect Dis 2024; 24:145. [PMID: 38291356 PMCID: PMC10826013 DOI: 10.1186/s12879-024-09025-5] [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: 12/09/2023] [Accepted: 01/17/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Niemann-Pick Disease type C is a fatal autosomal recessive lipid storage disorder caused by NPC1 or NPC2 gene mutations and characterized by progressive, disabling neurological deterioration and hepatosplenomegaly. Herein, we identified a novel compound heterozygous mutations of the NPC1 gene in a Chinese pedigree. CASE PRESENTATION This paper describes an 11-year-old boy with aggravated walking instability and slurring of speech who presented as Niemann-Pick Disease type C. He had the maternally inherited c.3452 C > T (p. Ala1151Val) mutation and the paternally inherited c.3557G > A (p. Arg1186His) mutation using next-generation sequencing. The c.3452 C > T (p. Ala1151Val) mutation has not previously been reported. CONCLUSIONS This study predicted that the c.3452 C > T (p. Ala1151Val) mutation is pathogenic. This data enriches the NPC1 gene variation spectrum and provides a basis for familial genetic counseling and prenatal diagnosis.
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Affiliation(s)
- Chaoxin Tao
- Department of Internal Medicine, Shijiazhuang Ping'an Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Min Zhao
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaohui Zhang
- Department of Internal Medicine, Shijiazhuang Ping'an Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jihong Hao
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Qiuyue Huo
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jie Sun
- Department of Ultrasound Diagnosis of Gynecology and Obstetrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiangtao Xing
- Department of Internal Medicine, Shijiazhuang Ping'an Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yuna Zhang
- Department of Internal Medicine, Shijiazhuang Ping'an Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jianhong Zhao
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
| | - Huaipeng Huang
- Department of Internal Medicine, Shijiazhuang Ping'an Hospital, Hebei Medical University, Shijiazhuang, Hebei, China.
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Mignani L, Guerra J, Corli M, Capoferri D, Presta M. Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish. Int J Mol Sci 2023; 24:ijms24054747. [PMID: 36902174 PMCID: PMC10002607 DOI: 10.3390/ijms24054747] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Sphingolipidoses are inborn errors of metabolism due to the pathogenic mutation of genes that encode for lysosomal enzymes, transporters, or enzyme cofactors that participate in the sphingolipid catabolism. They represent a subgroup of lysosomal storage diseases characterized by the gradual lysosomal accumulation of the substrate(s) of the defective proteins. The clinical presentation of patients affected by sphingolipid storage disorders ranges from a mild progression for some juvenile- or adult-onset forms to severe/fatal infantile forms. Despite significant therapeutic achievements, novel strategies are required at basic, clinical, and translational levels to improve patient outcomes. On these bases, the development of in vivo models is crucial for a better understanding of the pathogenesis of sphingolipidoses and for the development of efficacious therapeutic strategies. The teleost zebrafish (Danio rerio) has emerged as a useful platform to model several human genetic diseases owing to the high grade of genome conservation between human and zebrafish, combined with precise genome editing and the ease of manipulation. In addition, lipidomic studies have allowed the identification in zebrafish of all of the main classes of lipids present in mammals, supporting the possibility to model diseases of the lipidic metabolism in this animal species with the advantage of using mammalian lipid databases for data processing. This review highlights the use of zebrafish as an innovative model system to gain novel insights into the pathogenesis of sphingolipidoses, with possible implications for the identification of more efficacious therapeutic approaches.
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Gardin A, Mussini C, Héron B, Schiff M, Brassier A, Dobbelaere D, Broué P, Sevin C, Vanier MT, Habes D, Jacquemin E, Gonzales E. A Retrospective Multicentric Study of 34 Patients with Niemann-Pick Type C Disease and Early Liver Involvement in France. J Pediatr 2023; 254:75-82.e4. [PMID: 36265573 DOI: 10.1016/j.jpeds.2022.10.015] [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: 08/11/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 12/05/2022]
Abstract
OBJECTIVE To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder. STUDY DESIGN Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining. RESULTS At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68+ storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6 months of life, including 3 from liver involvement. In patients who survived beyond age 6 months (median follow-up, 6.1 years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients. CONCLUSIONS Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.
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Affiliation(s)
- Antoine Gardin
- Pediatric Hepatology and Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, European Reference Network RARE-LIVER, Filière de Santé des Maladies Rares du Foie de l'Enfant et de l'Adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France.
| | - Charlotte Mussini
- Department of Pathology, Bicêtre Hospital, Le Kremlin-Bicêtre, France
| | - Bénédicte Héron
- Department of Pediatric Neurology, Reference Center for Lysosomal Diseases, Armand Trousseau-La Roche Guyon Hospital, Assistance Publique-Hôpitaux de Paris, Fédération Hospitalo-Universitaire I2-D2, Sorbonne-Université, Paris, France
| | - Manuel Schiff
- Reference Center for Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Filière G2M, Paris, France; Inserm UMR S1163, Institut Imagine, Université Paris Cité, Paris, France
| | - Anaïs Brassier
- Reference Center for Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Filière G2M, Paris, France
| | - Dries Dobbelaere
- Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre University Children's Hospital and Research Team for Rare Metabolic and Developmental Diseases (RADEME), EA 7364 CHRU Lille, Lille, France; MetabERN
| | - Pierre Broué
- Department of Pediatric Hepatology, Reference Center for Inborn Error of Metabolism, Toulouse Children Hospital, Toulouse, France
| | - Caroline Sevin
- Department of Pediatric Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre, France
| | - Marie T Vanier
- Inserm U820, Laboratoire Gillet-Mérieux, Hospices Civils de Lyon, Lyon, France
| | - Dalila Habes
- Pediatric Hepatology and Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, European Reference Network RARE-LIVER, Filière de Santé des Maladies Rares du Foie de l'Enfant et de l'Adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, European Reference Network RARE-LIVER, Filière de Santé des Maladies Rares du Foie de l'Enfant et de l'Adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France; Inserm UMR S1193, Université Paris-Saclay, Hépatinov, Orsay, France
| | - Emmanuel Gonzales
- Pediatric Hepatology and Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, European Reference Network RARE-LIVER, Filière de Santé des Maladies Rares du Foie de l'Enfant et de l'Adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France; Inserm UMR S1193, Université Paris-Saclay, Hépatinov, Orsay, France
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4
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Sparks TN, Dugoff L. How to choose a test for prenatal genetic diagnosis: a practical overview. Am J Obstet Gynecol 2023; 228:178-186. [PMID: 36029833 PMCID: PMC9877133 DOI: 10.1016/j.ajog.2022.08.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/29/2022] [Accepted: 08/05/2022] [Indexed: 01/28/2023]
Abstract
Establishing the diagnosis of a fetal genetic disease in utero expands decision-making opportunities for individuals during pregnancy and enables providers to tailor prenatal care and surveillance to disease-specific risks. The selection of prenatal genetic tests is guided by key details from fetal imaging, family and obstetrical history, suspected diagnoses and mechanisms of disease, an accurate understanding of what abnormalities each test is designed to detect, and, at times, the gestational age at which testing is initiated. Pre- and posttest counseling, by or in conjunction with providers trained in genetics, ensure an accurate understanding of genetic tests, their potential results and limitations, estimated turnaround time for results, and the clinical implications of their findings. As prenatal diagnosis and testing options continue to expand rapidly, it is increasingly important for obstetrical providers to understand how to choose appropriate genetic testing and contextualize the clinical implications of their results.
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Affiliation(s)
- Teresa N Sparks
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA.
| | - Lorraine Dugoff
- Divisions of Reproductive Genetics and Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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5
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Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022; 14:1844-1861. [PMID: 36340750 PMCID: PMC9627439 DOI: 10.4254/wjh.v14.i10.1844] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/21/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
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Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad 500072, India
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Quelhas P, Jacinto J, Cerski C, Oliveira R, Oliveira J, Carvalho E, dos Santos J. Protocols of Investigation of Neonatal Cholestasis-A Critical Appraisal. Healthcare (Basel) 2022; 10:2012. [PMID: 36292464 PMCID: PMC9602084 DOI: 10.3390/healthcare10102012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/04/2022] Open
Abstract
Neonatal cholestasis (NC) starts during the first three months of life and comprises extrahepatic and intrahepatic groups of diseases, some of which have high morbimortality rates if not timely identified and treated. Prolonged jaundice, clay-colored or acholic stools, and choluria in an infant indicate the urgent need to investigate the presence of NC, and thenceforth the differential diagnosis of extra- and intrahepatic causes of NC. The differential diagnosis of NC is a laborious process demanding the accurate exclusion of a wide range of diseases, through the skillful use and interpretation of several diagnostic tests. A wise integration of clinical-laboratory, histopathological, molecular, and genetic evaluations is imperative, employing extensive knowledge about each evaluated disease as well as the pitfalls of each diagnostic test. Here, we review the difficulties involved in correctly diagnosing the cause of cholestasis in an affected infant.
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Affiliation(s)
- Patricia Quelhas
- Faculty of Health Sciences, Health Science Investigation Center of University of Beira Interior (CICS-UBI), 6200-506 Covilha, Portugal
| | - Joana Jacinto
- Medicine Department, University of Beira Interior (UBI), Faculty of Health Sciences, 6201-001 Covilha, Portugal
| | - Carlos Cerski
- Pathology Department of Universidade Federal do Rio Grande do Sul (UFRGS), Pathology Service of Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre 90035-903, Brazil
| | - Rui Oliveira
- Centro de Diagnóstico Histopatológico (CEDAP), 3000-377 Coimbra, Portugal
| | - Jorge Oliveira
- Center for Predictive and Preventive Genetics (CGPP), IBMC, UnIGENe, i3S, University of Porto, 4200-135 Porto, Portugal
| | - Elisa Carvalho
- Department of Gastroenterology and Hepatology, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Brasília 70330-150, Brazil
| | - Jorge dos Santos
- Faculty of Health Sciences, Health Science Investigation Center of University of Beira Interior (CICS-UBI), 6200-506 Covilha, Portugal
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7
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Neonatal cholestasis and Niemann-pick type C disease: A literature review. Clin Res Hepatol Gastroenterol 2021; 45:101757. [PMID: 34303826 DOI: 10.1016/j.clinre.2021.101757] [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: 09/08/2020] [Revised: 06/16/2021] [Accepted: 06/23/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Neonatal cholestasis (NC) is one of the most serious diseases in newborns and infants and results from metabolic disorders, such as Niemann-Pick type C (NPC), among other causes. OBJECTIVE We evaluated the incidence of NPC in our NC plus lysosomal storage disease (LSD) suspicious neonates and infants series. METHODS The study included children (≤3 years old) with a history of NC together with a suspicion of LSD, referred from Spanish Hospitals during the period 2011-2020. Screening for NPC was done by plasma biomarker assay (chitotriosidase activity and 7-ketocholesterol), and Sanger sequencing for NPC1 and NPC2 genes. RESULTS We screened NPC disease in 17 patients with NC plus organomegaly and that were LSD suspicious, finding 5 NPC patients (29.4%) and 2 carriers. CONCLUSIONS Our results emphasize the need to study NPC when NC and visceral enlargement arise in a newborn or infant.
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8
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Paget TL, Parkinson-Lawrence EJ, Orgeig S. The role of surfactant and distal lung dysfunction in the pathology of lysosomal storage diseases. CURRENT OPINION IN PHYSIOLOGY 2021. [DOI: 10.1016/j.cophys.2021.100467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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9
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Rodriguez-Gil JL, Baxter LL, Watkins-Chow DE, Johnson NL, Davidson CD, Carlson SR, Incao AA, Wallom KL, Farhat NY, Platt FM, Dale RK, Porter FD, Pavan WJ. Transcriptome of HPβCD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics. Hum Mol Genet 2021; 30:2456-2468. [PMID: 34296265 DOI: 10.1093/hmg/ddab194] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/20/2021] [Accepted: 06/29/2021] [Indexed: 11/12/2022] Open
Abstract
The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a compound currently under investigation in clinical trials. A total of 485 HPβCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of serum from Npc1m1N null mice treated with HPβCD and adeno-associated virus (AAV) gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPβCD treatment.
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Affiliation(s)
- Jorge L Rodriguez-Gil
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health.,Medical Scientist Training Program, University of Wisconsin-Madison School of Medicine and Public Health
| | - Laura L Baxter
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
| | - Dawn E Watkins-Chow
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
| | - Nicholas L Johnson
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
| | - Cristin D Davidson
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
| | - Steven R Carlson
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
| | - Arturo A Incao
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
| | | | | | - Nicole Y Farhat
- Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
| | | | - Ryan K Dale
- Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
| | - Forbes D Porter
- Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
| | - William J Pavan
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health
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10
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Bueno-Lozano O, Valle-Guillén S, Rodríguez G, López de Frutos L, Ventura-Faci P. [Neonatal-onset Niemann-Pick type C disease with COVID-19 infection]. An Pediatr (Barc) 2021:S1695-4033(21)00147-8. [PMID: 33832857 PMCID: PMC7931683 DOI: 10.1016/j.anpedi.2021.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/16/2021] [Indexed: 11/19/2022] Open
Abstract
Este artículo ha sido retirado a petición del autor. La editorial lamenta los inconvenientes ocasionados. Puede consultar la política de Elsevier sobre la retirada de artículos en https://www.elsevier.com/about/our-business/policies/article-withdrawal .
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Affiliation(s)
- Olga Bueno-Lozano
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Facultad de Medicina, Universidad de Zaragoza, España; Instituto Investigación Sanitaria Aragón (IIS Aragón), España
| | - Sofía Valle-Guillén
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Facultad de Medicina, Universidad de Zaragoza, España; Instituto Investigación Sanitaria Aragón (IIS Aragón), España
| | - Gerardo Rodríguez
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Facultad de Medicina, Universidad de Zaragoza, España; Instituto Investigación Sanitaria Aragón (IIS Aragón), España; Red de Salud Materno-infantil y del Desarrollo (SAMID), RETICS financiada por el the PN I+D+I 2018-2021, España
| | - Laura López de Frutos
- Instituto Investigación Sanitaria Aragón (IIS Aragón), España; Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG), España.
| | - Purificación Ventura-Faci
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Facultad de Medicina, Universidad de Zaragoza, España; Instituto Investigación Sanitaria Aragón (IIS Aragón), España; Red de Salud Materno-infantil y del Desarrollo (SAMID), RETICS financiada por el the PN I+D+I 2018-2021, España
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11
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Understanding and Treating Niemann-Pick Type C Disease: Models Matter. Int J Mol Sci 2020; 21:ijms21238979. [PMID: 33256121 PMCID: PMC7730076 DOI: 10.3390/ijms21238979] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.
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12
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Yıldız Y, Sivri HS. Inborn errors of metabolism in the differential diagnosis of fatty liver disease. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:3-16. [PMID: 32009609 DOI: 10.5152/tjg.2019.19367] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease across all age groups. Obesity, diabetes, and metabolic syndrome, are the primary causes that are closely linked with the development of NAFLD. However, in young children, rare inborn errors of metabolism are predominant secondary causes of NAFLD. Furthermore, inborn errors of metabolism causing hepatosteatosis are often misdiagnosed as NAFLD in adolescents and adults. Many inborn errors of metabolism are treatable disorders and therefore require special consideration. This review aims to summarize the basic characteristics and diagnostic clues of inborn errors of metabolism associated with fatty liver disease. A suggested clinical and laboratory diagnostic approach is also discussed.
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Affiliation(s)
- Yılmaz Yıldız
- Pediatric Metabolic Diseases Unit, Dr. Sami Ulus Training and Research Hospital for Maternity and Children's Health and Diseases, Ankara, Turkey
| | - Hatice Serap Sivri
- Division of Metabolic Diseases, Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey
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13
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Santos Silva E, Almeida A, Frutuoso S, Martins E, Valente MJ, Santos-Silva A, Lopes AI. Neonatal Cholestasis Over Time: Changes in Epidemiology and Outcome in a Cohort of 154 Patients From a Portuguese Tertiary Center. Front Pediatr 2020; 8:351. [PMID: 32695736 PMCID: PMC7338938 DOI: 10.3389/fped.2020.00351] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/27/2020] [Indexed: 01/23/2023] Open
Abstract
Introduction: In the last two decades there have been advances in the diagnosis and management of neonatal cholestasis, which may have changed its epidemiology, diagnostic accuracy, outcomes, and survival. Our goal was to characterize these changes over time in our setting. Methods: Retrospective cohort study in a tertiary center, enrolling patients born between January 1985 and October 2019. The cohort was divided into two periods, before (A; n = 67) and after (B; n = 87) the year 2000; and in two groups, according to patient's outcome (favorable, unfavorable). Overall survival and survival with and without orthotopic liver transplant (OLT) were evaluated in the two periods (A and B) and in different subgroups of underlying entities. Results: We found that the age of cholestasis recognition decreased significantly from period A to period B [median 43 days and 22 days, respectively, (p < 0.001)]; the changes in epidemiology were relevant, with a significant decrease in alpha-1-antitrypsin deficiency (p < 0.001) and an increase in transient cholestasis (p = 0.004). A next-generation sequencing (NGS) panel available since mid-2017 was applied to 13 patients with contributory results in 7, but, so far, only in 2 patients led to conclusive diagnosis of underlying entities. The number of cases of idiopathic cholestasis did not vary significantly. Over time there was no significant change in the outcome (p = 0.116). Overall survival and survival without OLT had no significant improvement during the period of observation (in periods A and B, 86 vs. 88%, and 85 vs. 87%, respectively). However, in period B, with OLT we achieved the goal of 100% of survival rate. Conclusions: Our data suggest that transient cholestasis became a very important subset of neonatal cholestasis, requiring specific guidance. The NGS panels can provide important inputs on disease diagnosis but, if applied without strict criteria and expertise, they can open a Pandora's box due to misinterpretation. Despite all the advances in accurate diagnosis and timely management-including early recognition of cholestasis-the improvement in patient outcomes and survival were still not significant.
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Affiliation(s)
- Ermelinda Santos Silva
- Paediatric Gastroenterology Unit, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal.,Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.,UCIBIO-REQUIMTE, Laboratory of Biochemistry, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Alexandra Almeida
- Neonatology Unit, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Simão Frutuoso
- Neonatology Unit, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Esmeralda Martins
- Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.,Metabolic Diseases Reference Center, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Maria João Valente
- UCIBIO-REQUIMTE, Laboratory of Biochemistry, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Alice Santos-Silva
- UCIBIO-REQUIMTE, Laboratory of Biochemistry, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Ana Isabel Lopes
- Paediatric Gastroenterology Unit, Hospital Universitário de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.,Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology. J Clin Med 2019; 9:jcm9010012. [PMID: 31861571 PMCID: PMC7019814 DOI: 10.3390/jcm9010012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 12/11/2019] [Accepted: 12/17/2019] [Indexed: 12/17/2022] Open
Abstract
The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.
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15
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Bräuer AU, Kuhla A, Holzmann C, Wree A, Witt M. Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1. Int J Mol Sci 2019; 20:ijms20184392. [PMID: 31500175 PMCID: PMC6771135 DOI: 10.3390/ijms20184392] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann–Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.
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Affiliation(s)
- Anja U Bräuer
- Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany.
- Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany.
| | - Angela Kuhla
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany.
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
| | - Carsten Holzmann
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany.
| | - Andreas Wree
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany.
| | - Martin Witt
- Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany.
- Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany.
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16
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Gadolinium Chloride Rescues Niemann⁻Pick Type C Liver Damage. Int J Mol Sci 2018; 19:ijms19113599. [PMID: 30441844 PMCID: PMC6274821 DOI: 10.3390/ijms19113599] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/01/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023] Open
Abstract
Niemann–Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68—A marker of Kupffer cells in the liver—and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.
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17
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Tseng WC, Loeb HE, Pei W, Tsai-Morris CH, Xu L, Cluzeau CV, Wassif CA, Feldman B, Burgess SM, Pavan WJ, Porter FD. Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds. Dis Model Mech 2018; 11:11/9/dmm034165. [PMID: 30135069 PMCID: PMC6176986 DOI: 10.1242/dmm.034165] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/11/2018] [Indexed: 12/27/2022] Open
Abstract
Niemann-Pick disease type C1 (NPC1) is a rare autosomal recessive lysosomal storage disease primarily caused by mutations in NPC1. NPC1 is characterized by abnormal accumulation of unesterified cholesterol and glycolipids in late endosomes and lysosomes. Common signs include neonatal jaundice, hepatosplenomegaly, cerebellar ataxia, seizures and cognitive decline. Both mouse and feline models of NPC1 mimic the disease progression in humans and have been used in preclinical studies of 2-hydroxypropyl-β-cyclodextrin (2HPβCD; VTS-270), a drug that appeared to slow neurological progression in a Phase 1/2 clinical trial. However, there remains a need to identify additional therapeutic agents. High-throughput drug screens have been useful in identifying potential therapeutic compounds; however, current preclinical testing is time and labor intensive. Thus, development of a high-capacity in vivo platform suitable for screening candidate drugs/compounds would be valuable for compound optimization and prioritizing subsequent in vivo testing. Here, we generated and characterize two zebrafish npc1-null mutants using CRISPR/Cas9-mediated gene targeting. The npc1 mutants model both the early liver and later neurological disease phenotypes of NPC1. LysoTracker staining of npc1 mutant larvae was notable for intense staining of lateral line neuromasts, thus providing a robust in vivo screen for lysosomal storage. As a proof of principle, we were able to show that treatment of the npc1 mutant larvae with 2HPβCD significantly reduced neuromast LysoTracker staining. These data demonstrate the potential value of using this zebrafish NPC1 model for efficient and rapid in vivo optimization and screening of potential therapeutic compounds. This article has an associated First Person interview with the first author of the paper. Summary: A zebrafish genetic model of Niemann-Pick disease type C1 is suitable for performing in vivo screening of candidate therapeutic compounds by examining LysoTracker staining intensity in neuromasts.
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Affiliation(s)
- Wei-Chia Tseng
- Section on Molecular Dysmorphology, Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Hannah E Loeb
- Section on Molecular Dysmorphology, Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Wuhong Pei
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Chon-Hwa Tsai-Morris
- Zebrafish Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Lisha Xu
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Celine V Cluzeau
- Section on Molecular Dysmorphology, Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Christopher A Wassif
- Section on Molecular Dysmorphology, Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Benjamin Feldman
- Zebrafish Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Shawn M Burgess
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - William J Pavan
- Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
| | - Forbes D Porter
- Section on Molecular Dysmorphology, Division of Translational Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
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