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. 2024 Jun;39(6):983-995.
doi: 10.1002/mds.29754. Epub 2024 Apr 6.

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

Rauan Kaiyrzhanov  1 , Juan Darío Ortigoza-Escobar  2   3   4 , Brett W Stringer  5 , Manizha Ganieva  6 , Vykuntaraju K Gowda  7 , Varunvenkat M Srinivasan  7 , Alfons Macaya  4   8 , Andreas Laner  9 , Enas Onbool  10 , Randa Al-Shammari  11 , Mohammed Al-Owain  11   12 , Nicolas Deconinck  13 , Catheline Vilain  14 , Pauline Dontaine  13 , Eleanor Self  1 , Rabia Akram  1   15 , Ghulam Hussain  15 , Shahid Mahmood Baig  16   17 , Javed Iqbal  18 , Vincenzo Salpietro  1 , Maedeh Neshatdoust  19 , Mahboubeh Kasiri  20 , Gozde Yesil  21 , Turkan Uygur  22 , Karen Pysden  23 , Ian R Berry  24 , Cesar Augusto Alves  25 , Jean Giacomotto  5   26 , Henry Houlden  1 , Reza Maroofian  1
Affiliations

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

Rauan Kaiyrzhanov et al. Mov Disord. 2024 Jun.

Abstract

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.

Keywords: CA8; ataxia; cerebellar atrophy; vermis atrophy.

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