Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia
Por:
Kaiyrzhanov R, Ortigoza-Escobar JD, Stringer BW, Ganieva M, Gowda VK, Srinivasan VM, Macaya A, Laner A, Onbool E, Al-Shammari R, Al-Owain M, Deconinck N, Vilain C, Dontaine P, Self E, Akram R, Hussain G, Baig SM, Iqbal J, Salpietro V, Neshatdoust M, Kasiri M, Yesil G, Uygur T, Pysden K, Berry IR, Alves CA, Giacomotto J, Houlden H and Maroofian R
Publicada:
1 jun 2024
Ahead of Print:
1 abr 2024
Resumen:
Background: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). Objectives: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. Methods: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Results: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Conclusion: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Filiaciones:
Kaiyrzhanov R:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Ortigoza-Escobar JD:
U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
Movement Disorders Unit, Pediatric Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain
Stringer BW:
Griffith Institute for Drug Discovery, Centre for Cellular Phenomics, School of Environment and Science Griffith University, Brisbane, Queensland, Australia
Ganieva M:
Avicenna Tajik State Medical University, Department of Neurology and Medical Genetics, Dushanbe, Tajikistan
Gowda VK:
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
Srinivasan VM:
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
Macaya A:
European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain
Department of Paediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Laner A:
MGZ - Medical Genetics Centre, Munich, Germany
Onbool E:
Neurology department, King Abdulaziz Specialist Hospital, Skaka Aljouf, Saudi Arabia
Al-Shammari R:
Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Al-Owain M:
Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Deconinck N:
Centre de Référence des Maladies Neuromusculaires et Service de Neurologie Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium
Vilain C:
Department of Genetics, Hôpital Universitaire Reine Fabiola (HUDERF)
Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium
Dontaine P:
Centre de Référence des Maladies Neuromusculaires et Service de Neurologie Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium
Self E:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Akram R:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Neurochemical biology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
Hussain G:
Neurochemical biology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
Baig SM:
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, Faisalabad, Pakistan
Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
Iqbal J:
Department of Neurology, Allied Hospital, Faisalabad Medical University, Faisalabad, Pakistan
Salpietro V:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Neshatdoust M:
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
Kasiri M:
School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
Yesil G:
Department of Medical Genetics, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Uygur T:
Department of Pediatric Neurology, Bezmialem Vakif University, Istanbul, Turkey
Pysden K:
Paediatric Neurology Department, Leeds Teaching Hospitals, Leeds General Infirmary, Leeds, United Kingdom
Berry IR:
Yorkshire and North East Genomic Laboratory Hub Central Laboratory, Leeds, United Kingdom
Alves CA:
Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Giacomotto J:
Griffith Institute for Drug Discovery, Centre for Cellular Phenomics, School of Environment and Science Griffith University, Brisbane, Queensland, Australia
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
Houlden H:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Maroofian R:
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Green Submitted, hybrid
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