The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

التفاصيل البيبلوغرافية
العنوان:	The expanding clinical and genetic spectrum of DYNC1H1-related disorders.
المؤلفون:	Möller B; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Becker LL; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.; Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children, 13353 Berlin, Germany.; Charité-Universitätsmedizin Berlin, Institute for Cell Biology and Neurobiology, 13353 Berlin, Germany., Saffari A; Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University, 69120 Heidelberg, Germany., Afenjar A; Sorbonne University, Reference Center for Malformations and Congenital Diseases of the Cerebellum and Intellectual Disabilities of Rare Causes, Department of Genetics and Medical Embryology, Trousseau Hospital Paris, 75012 Paris, France., Coci EG; Department of Paediatrics, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany.; Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark., Williamson R; Akron Children's Hospital Genetic Center, Akron, 44308 OH, USA., Ward-Melver C; Service de pédiatrie, CHU de Nantes, 44000 Nantes, France., Gibaud M; Service de pédiatrie, CHU de Nantes, 44000 Nantes, France., Sedláčková L; Neurogenetic Laboratory, Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Full Member of the ERN EpiCARE, 150 06 Prague, Czech Republic., Laššuthová P; Neurogenetic Laboratory, Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Full Member of the ERN EpiCARE, 150 06 Prague, Czech Republic., Libá Z; Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Full Member of the ERN EpiCARE, 150 06 Prague, Czech Republic., Vlčková M; Biology and Medical Genetics, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Full Member of the ERN EpiCARE, 150 06 Prague, Czech Republic., William N; Center for Individualized Medicine, Mayo Clinic, Rochester, 55901 MN, USA., Klee EW; Departments of Clinical Genomics and Neurology, Mayo Clinic, Rochester, 55901 MN, USA., Gavrilova RH; Departments of Clinical Genomics and Neurology, Mayo Clinic, Rochester, 55901 MN, USA., Lévy J; Genetics Department, AP-HP, Robert-Debré University Hospital, 75019 Paris, France., Capri Y; Genetics Department, AP-HP, Robert-Debré University Hospital, 75019 Paris, France., Scavina M; Nemours Children's Health, AI duPont Division of Neurology, Wilmington, 19803 DE, USA., Körner RW; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Valuvullah Z; Center for Mendelian Genomics, Broad Institute Harvard, Cambridge, 02142 MA, USA., Weiß C; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.; Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children, 13353 Berlin, Germany., Möller GM; Berlin University of Applied Sciences and Technology, 10587 Berlin, Germany., Thiel M; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Sinnema M; Maastricht University Medical Center, Department of Clinical Genetics, 6229 Maastricht, The Netherlands., Kamsteeg EJ; Radboud University Medical Center, 6525 Nijmegen, The Netherlands., Donkervoort S; National Institute of Neurological Disorders and Stroke, Bethesda, 20892 MD, USA., Duboc V; Department of Medical Genetics, Université Côte D'Azur, Centre Hospitalier Universitaire Nice, 06000 Nice, France., Zaafrane-Khachnaoui K; Department of Medical Genetics, Université Côte D'Azur, Centre Hospitalier Universitaire Nice, 06000 Nice, France., Elkhateeb N; Department of Clinical Genetics, Cambridge University Hospitals NHS Trust, Cambridge CB2 3EH, UK.; Department of Pediatrics, Pediatric Neurology and Metabolic Medicine unit, Kasr Al-Ainy School of Medicine, Cairo University, 4390330 Cairo, Egypt., Selim L; Department of Pediatrics, Pediatric Neurology and Metabolic Medicine unit, Kasr Al-Ainy School of Medicine, Cairo University, 4390330 Cairo, Egypt., Margot H; Department of Medical Genetics, University Hospital of Bordeaux, 33076 Bordeaux, France., Marin V; Department of Medical Genetics, University Hospital of Bordeaux, 33076 Bordeaux, France., Beneteau C; Department of Medical Genetics, University Hospital of Bordeaux, 33076 Bordeaux, France., Isidor B; Nantes University, CHU de Nantes, Genetics department, 44000 Nantes, France., Cogne B; Nantes University, CHU de Nantes, Genetics department, 44000 Nantes, France., Keren B; Genetic Department, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, 75013 Paris, France., Küsters B; Department of Pathology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 Nijmegen, The Netherlands., Beggs AH; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, 02445 MA, USA., Genetti CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, 02445 MA, USA., Nicolai J; Maastricht University Medical Center, Department of Neurology, 6229 Maastricht, the Netherlands., Dötsch J; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Koy A; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Bönnemann CG; National Institute of Neurological Disorders and Stroke, Bethesda, 20892 MD, USA., von der Hagen M; Department of Neuropediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany., von Kleist-Retzow JC; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany., Voermans N; The Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, the Netherlands., Jungbluth H; Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London SE1 7EH, UK.; Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London SE1 1YR, UK., Dafsari HS; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London SE1 7EH, UK.; Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London SE1 1YR, UK.; Max-Planck-Institute for Biology of Ageing, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), 50931 Cologne, Germany.
المصدر:	Brain : a journal of neurology [Brain] 2024 Jun 08. Date of Electronic Publication: 2024 Jun 08.
Publication Model:	Ahead of Print
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
أسماء مطبوعة:	Publication: Oxford : Oxford University Press Original Publication: London.
مستخلص:	Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
فهرسة مساهمة:	Keywords: autophagy; intracellular trafficking; neurodevelopmental disorders; viral immunity
تواريخ الأحداث:	Date Created: 20240607 Latest Revision: 20240607
رمز التحديث:	20240608
DOI:	10.1093/brain/awae183
PMID:	38848546
قاعدة البيانات:	MEDLINE

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تدمد:	1460-2156
DOI:	10.1093/brain/awae183