The inherited cerebellar ataxias: an update

Abstract

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.

Keywords: Cerebellar ataxia; Genetics; Next generation sequencing; Phenotype.

Fig. 1

Flowchart of the diagnostic process in cerebellar ataxias. This flowchart shows the steps in evaluating a patient with cerebellar ataxia based on clinical and family history, physical evaluation and paraclinical tests. First, the onset should be differentiated between acute and subacute/chronic; second, the acquired causes have to be ruled out by paraclinical investigations as neuroimaging, blood and cerebrospinal fluid exams; third, if family history is positive for inherited cerebellar ataxia, the clinician should determine the transmission pattern by pedigree in three generations at least. Sporadic forms should be explored as recessive ones especially in the case of early-onset (before the age of 40). The main laboratory investigations for the diagnosis of autosomal-recessive cerebellar ataxias are reported in the table on the left. *For sporadic patients with unknown or censored family history, autosomal forms should be also considered. AD autosomal dominant, AR autosomal recessive, α-FP alpha-fetoprotein, CoQ10 Coenzyme Q10, Ig Immunoglobulin, Mt mitochondrial