Abstract
ABSTRACT Background: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. Methods: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In‐depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. Results: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task‐induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. Conclusion: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Highlights
One mutation was located in the catalytic domain in exon 11 of protein kinase Cg gene (PRKCG) (Fig. 1B)
We studied a large cohort (n 5 194) of mainly pure, autosomal dominant cerebellar ataxia cohort negative for trinucleotide repeats and identified 13 families with disease-causing mutations in PRKCG with a variable spectrum of disease phenotype and severity
In the 13 families with PRKCG mutations, we identified 10 unique pathogenic variants suggesting that recurrent PRKCG mutations are infrequent
Summary
Proband cases with autosomal dominant, mainly pure, cerebellar ataxia were recruited with informed consents. Most of the families were of European ancestry (n 5 194, of which 190 were British, 3 Danish, and 1 Italian). All cases had comprehensive phenotyping performed by neurogenetics specialists. Ataxia was quantified in 17 cases using the validated Scale for Assessment and Rating of Ataxia (SARA).[10] Pure phenotype was defined as cerebellar syndrome, with brisk reflexes and neurogenic bladder accepted as additional features. Complex phenotype was defined as cases with cerebellar syndrome, plus at least 1 other neurological sign that cannot be explained by associated comorbidities. Disability score was defined as follows: 0 5 asymptomatic, 1 5 able to walk but difficulty with running, 2 5 uses one stick and/or orthosis, 3 5 uses 2 sticks/walker, 4 5 unable to walk, uses wheelchair
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