CA8-related cerebellar ataxia (CAMRQ3) is caused by biallelic pathogenic and likely pathogenic variants in CA8. The proposed molecular mechanism is loss of function, with clinical precedent for truncating variants causing disease and a spontaneous mouse model supporting a loss of function mechanism.
To date, 8 pathogenic or likely pathogenic variants in CA8 (3 truncating, 4 missense, 1 canonical splice) have been reported in association with the CAMRQ3 phenotype [Clinvar, Richmond et al 2019). Given the small number of cases, there is no established genotype phenotype correlation.
The ataxic phenotype in a compatible mouse model is mediated through disordered granule cell proliferation and circuit patterning of cerebellar Purkinje cells, providing a clue to the pathogenesis of this condition.
The diagnosis of CA8-related cerebellar ataxia is established in a proband with characteristic clinical features and biallelic (homozygous or compound heterozygous) pathogenic variants in CA8. Diagnostic testing approaches may include targeted gene panel testing or comprehensive genomic testing (whole exome sequencing, whole genome sequencing) evaluating genes associated with cerebellar hypoplasia and/or inherited ataxias. It is recommended that CA8 be included in commercial gene panels and virtual gene lists targeting cerebellar ataxia.
CA8