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Open Access 04-08-2022 | Blepharospasm | Original Communication

Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study

Authors: Megan E. Wadon, Eilidh Fenner, Kimberley M. Kendall, Grace A. Bailey, Cynthia Sandor, Elliott Rees, Kathryn J. Peall

Published in: Journal of Neurology | Issue 12/2022

Abstract

The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice.

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Title: Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
Authors: Megan E. Wadon
Eilidh Fenner
Kimberley M. Kendall
Grace A. Bailey
Cynthia Sandor
Elliott Rees
Kathryn J. Peall
Publication date: 04-08-2022
Publisher: Springer Berlin Heidelberg
Keywords: Blepharospasm
Torticollis Spasticus
Blepharospasm
Dystonia
Tremor
Published in: Journal of Neurology / Issue 12/2022
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-022-11307-4

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Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study

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