Complicated paroxysmal kinesigenic dyskinesia associated with
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
SACS
mutation
paroxysmal kinesigenic dyskinesia (PKD)
Journal
Annals of translational medicine
ISSN: 2305-5839
Titre abrégé: Ann Transl Med
Pays: China
ID NLM: 101617978
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
entrez:
15
2
2020
pubmed:
15
2
2020
medline:
15
2
2020
Statut:
ppublish
Résumé
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by pathogenic variants in the SACS gene and is characterized by ataxia, peripheral neuropathy, pyramidal impairment and episodic conditions such as epilepsy. Paroxysmal kinesigenic dyskinesia (PKD) had not been previously described in ARSACS. We analyzed clinical manifestations and performed whole-exome sequencing (WES) in two independent patients with ARSACS and PKD. Both patients' parents were unaffected. Genetic data were filtered for potential pathogenic variants, searching for de novo mutations suggestive of a dominant disease model or homozygous and compound heterozygous variants of a recessive model. Potential mutations that existed in both patients were generated and subjected to Sanger sequencing. The WES results of 163 PKD patients without additional symptoms from previous experiments were also reviewed. Novel compound heterozygous mutations in the SACS gene were identified in Patient 1 (p.P3007S and p.H3392fs), and a novel homozygous truncating mutation (p.W1376X) was identified in Patient 2. In both patients, each mutant allele was inherited from one of his or her unaffected parents. All 3 mutations were absent in 196 ethnic-matched control chromosomes or in data from the 1000 Genomes Project. No pathogenic variants associated with paroxysmal diseases, especially PKD and episodic ataxia, were identified. In PKD patients without additional symptoms, no homozygous or compound heterozygous variants in the SACS gene were detected. This study expands the clinical phenotype of ARSACS and suggests the inclusion of
Sections du résumé
BACKGROUND
BACKGROUND
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by pathogenic variants in the SACS gene and is characterized by ataxia, peripheral neuropathy, pyramidal impairment and episodic conditions such as epilepsy. Paroxysmal kinesigenic dyskinesia (PKD) had not been previously described in ARSACS.
METHODS
METHODS
We analyzed clinical manifestations and performed whole-exome sequencing (WES) in two independent patients with ARSACS and PKD. Both patients' parents were unaffected. Genetic data were filtered for potential pathogenic variants, searching for de novo mutations suggestive of a dominant disease model or homozygous and compound heterozygous variants of a recessive model. Potential mutations that existed in both patients were generated and subjected to Sanger sequencing. The WES results of 163 PKD patients without additional symptoms from previous experiments were also reviewed.
RESULTS
RESULTS
Novel compound heterozygous mutations in the SACS gene were identified in Patient 1 (p.P3007S and p.H3392fs), and a novel homozygous truncating mutation (p.W1376X) was identified in Patient 2. In both patients, each mutant allele was inherited from one of his or her unaffected parents. All 3 mutations were absent in 196 ethnic-matched control chromosomes or in data from the 1000 Genomes Project. No pathogenic variants associated with paroxysmal diseases, especially PKD and episodic ataxia, were identified. In PKD patients without additional symptoms, no homozygous or compound heterozygous variants in the SACS gene were detected.
CONCLUSIONS
CONCLUSIONS
This study expands the clinical phenotype of ARSACS and suggests the inclusion of
Identifiants
pubmed: 32055599
doi: 10.21037/atm.2019.11.31
pii: atm-08-01-8
pmc: PMC6995733
doi:
Types de publication
Journal Article
Langues
eng
Pagination
8Informations de copyright
2020 Annals of Translational Medicine. All rights reserved.
Déclaration de conflit d'intérêts
Conflicts of Interest: The authors have no conflicts of interest to declare.
Références
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1661-6
pubmed: 22307627
PLoS One. 2013 Jun 13;8(6):e66145
pubmed: 23785480
Neurol Genet. 2016 Jun 23;2(4):e83
pubmed: 27433545
J Neurol Sci. 2016 Dec 15;371:105-111
pubmed: 27871429
Eur J Neurol. 2013 Nov;20(11):1486-91
pubmed: 23800155
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Neurology. 2010 Sep 28;75(13):1181-8
pubmed: 20876471
Genome Biol. 2009;10(3):R25
pubmed: 19261174
J Neuroimaging. 2013 Jan;23(1):82-5
pubmed: 22268491
Hum Mol Genet. 2015 Feb 1;24(3):727-39
pubmed: 25260547
Mov Disord. 2018 Mar;33(3):459-467
pubmed: 29356177
Ann Neurol. 2016 Mar;79(3):428-36
pubmed: 26677014
Nat Genet. 2000 Feb;24(2):120-5
pubmed: 10655055
Ann Neurol. 2015 Dec;78(6):871-86
pubmed: 26288984
Parkinsonism Relat Disord. 2011 Jul;17(6):418-22
pubmed: 21450511
Nat Genet. 2011 Nov 20;43(12):1252-5
pubmed: 22101681
J Neurol. 2015 Dec;262(12):2755-63
pubmed: 26530509
J Neurol Neurosurg Psychiatry. 2013 Jan;84(1):114-6
pubmed: 23123642