Autosomal dominant cerebellar ataxias: new genes and progress towards treatments

Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1 , SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. Given this extreme clinical and genetic heterogeneity, genome sequencing should become the diagnostic tool of choice but is still not available in many clinical settings. Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.

Automated summary

Dominantly inherited spinocerebellar ataxias (SCAs) exhibit phenotypic variation and can be caused by multiple potentially pathogenic variants. Genome sequencing should be the preferred diagnostic tool due to the extreme clinical and genetic heterogeneity, but its availability is limited. Although treatments like riluzole and transcranial direct current stimulation have been tested, their efficacy remains conflicting. Biomarkers, such as neurofilament light chain and brain MRI, should be used to assess preataxic carriers and monitor target engagement by gene therapies.