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Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14.

ABSTRACT: BACKGROUND:Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase C? 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 C? gene. A total of 10 unique protein kinase C? 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 C? 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 C? 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.

SUBMITTER: Chelban V

PROVIDER: S-EPMC6175136 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14.

Chelban Viorica V Wiethoff Sarah S Fabian-Jessing Bjørn K BK Haridy Nourelhoda A NA Khan Alaa A Efthymiou Stephanie S Becker Esther B E EBE O'Connor Emer E Hersheson Joshua J Newland Katrina K Hojland Allan Thomas AT Gregersen Pernille A PA Lindquist Suzanne G SG Petersen Michael B MB Nielsen Jørgen E JE Nielsen Michael M Wood Nicholas W NW Giunti Paola P Houlden Henry H

Movement disorders : official journal of the Movement Disorder Society 20180330 7

<h4>Background</h4>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.<h4>Methods</h4>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 inve ...[more]

PMID: 29603387

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Project description:Importance:Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives:To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants:This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures:The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results:The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of ?-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P?<?.01). Decreased albumin levels (??=?-0.532) and elevated AFP levels (??=?0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P?<?.01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P?<?.001). Conclusions and Relevance:The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.

Dataset Information

Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14.

Publications

Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14.

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