Novel genotype-phenotype and MRI correlations in a large cohort of patients with mutations.

Objective: To clinically, genetically, and radiologically characterize a large cohort of patients.

Methods: We used data from next-generation sequencing panels for ataxias and hereditary spastic paraplegia to identify a characteristic phenotype that helped direct genetic testing for variations in . We analyzed MRI. We reviewed all published mutations for correlations.

Results: We identified 42 cases with biallelic mutations, including 7 novel mutations, including a large multi-exon deletion, representing one of the largest cohorts so far described. We identified a characteristic phenotype comprising cerebellar ataxia with prominent cerebellar dysarthria, mild lower limb spasticity, and a waddling gait, predominantly from a cohort of idiopathic ataxia. We report a rare brain MRI finding of dentate nucleus hyperintensity on T2 sequences with mutations. We confirm that the c.1529C>T allele is frequently present in patients with long-standing British ancestry. Based on the findings of the present study and existing literature, we confirm that patients with homozygous mutations involving the M41 peptidase domain of have a younger age at onset compared to individuals with mutations elsewhere in the gene (14 years difference, < 0.034), whereas c.1529C>T compound heterozygous mutations are associated with a younger age at onset compared to homozygous cases (5.4 years difference, < 0.022).

Conclusions: Mutant is common in sporadic ataxia. In patients with British ancestry, c.1529C>T allele represents the most frequent mutation. mutations can be clinically predicted by the characteristic hybrid spastic-ataxic phenotype described above, along with T2 hyperintensity of the dentate nucleus on MRI.