Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2022-12-01
Date Acceptance
2022-07-21
Citation
Journal of Neurology, 2022, 269 (12), pp.6436-6451
ISSN
0340-5354
Publisher
Springer
Start Page
6436
End Page
6451
Journal / Book Title
Journal of Neurology
Volume
269
Issue
12
Copyright Statement
© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/35925398
PII: 10.1007/s00415-022-11307-4
Subjects
ASSOCIATIONS
BLEPHAROSPASM
CERVICAL DYSTONIA
Clinical Neurology
Cognition
DISEASE
DISTURBANCES
Dystonia
Life Sciences & Biomedicine
Neurosciences & Neurology
Pain
PAIN
PATTERNS
Psychiatric
QUALITY-OF-LIFE
Science & Technology
Sleep
SLEEP
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2022-08-04