Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia

Abstract

Ataxia; Cerebellar atrophy; Vermis atrophy

Atàxia; Atròfia cerebel·losa; Atròfia del vermis

Ataxia; Atrofia cerebelosa; Atrofia del vermis

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. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The authors declare that there are no other conflicts of interest relevant to this work. This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943, MR/V012177/1), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia United Kingdom (UK), MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). H.H. and R.K. are supported by Global Parkinson's Genetic Program (GP2) The Michael J. Fox Foundation (MJFF) grant MJFF-022153. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was also supported by grants from the Australian National Health and Medical Research Council (1165850 and 1174145 to J.G.).