Journal Article

The inherited cerebellar ataxias: an update

Durr, Alexandra, Wirth, Thomas, Coarelli, Giulia, Koenig, Michel, Tranchant, Christine, Anheim, Mathieu

2023

Overview

This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer Verlag
• Subject: Antisense oligonucleotides / Antisense therapy / Ataxia / Ataxia - genetics / Cerebellar ataxia / Cerebellar Ataxia - diagnosis / Cerebellar Ataxia - genetics / Cerebellar Ataxia - therapy / Cerebellum / Cognitive ability / Diagnosis / Disease management / Fragile X syndrome / Friedreich Ataxia - diagnosis / Friedreich Ataxia - genetics / Friedreich Ataxia - therapy / Friedreich's ataxia / Gene therapy / Genetic analysis / Genetic counseling / Heredity / Humans / Intellectual disabilities / Life Sciences / Malignancy / Medicine / Medicine & Public Health / Mutation / Neurology / Neuroradiology / Neurosciences / Next-generation sequencing / Nomenclature / Pathogenicity / Phenotypes / Polyglutamine / Review / Spinocerebellar ataxia / Spinocerebellar Ataxias - genetics / Tremor / Trinucleotide repeat diseases