CACNA1B gene variants in adult-onset isolated focal dystonia

Human molecular genetics, 2015

Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single-channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability charac...

International Journal of Molecular Sciences

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such stu...

Human Molecular Genetics, 2015

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in approximately 30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with 5 subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available datasets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1/520; 0.19%) and healthy controls (1/489; 0.2%).

Movement Disorders, 2021

Mainly due to the advent of next-generation se-quencing (NGS), the field of genetics of dystonia has rapidly grown in recent years, which led to the discovery of a number of novel dystonia genes and the development of a new classification and nomenclature for inherited dystonias. In addition, new findings from both in vivo and in vitro studies have been published on the role of previously known dystonia genes, extending our understanding of the pathophysiology of dys-tonia. We here review the current knowledge and recent findings in the known genes for isolated dystonia TOR1A, THAP1, and GNAL as well as for the combined dystonias due to mutations in GCH1, ATP1A3, and SGCE. We present confirmatory evidence for a role of dystonia genes that had not yet been unequivocally established including PRKRA, TUBB4A, ANO3, and TAF1. We finally discuss selected novel genes for dystonia such as KMT2B and VAC14 along with the challenges for gene identification in the NGS era and the translational importance of dystonia genetics in clinical practice.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

2008

We describe a large family with a primary focal dystonia from a small Dutch village on a former island. Twenty-four individuals spanning three generations were examined by two movement-disorder neurologists. Two other movement-disorder neurologists evaluated the videos independently. Subjects were classified as "affected," "possibly affected," or "not affected." A diagnosis was defined if all the neurologists agreed on the definition. Eight definitely affected and four possibly affected subjects were detected. Clinical presentation consisted of mild cranio-cervical-brachial dystonia. Mean age at onset was 45.5 years (range, 39-56). Mean BFMDRS motor score was 4.4 (range, 1-8). Mean TWSTRS score (part I) was 11.3 (range, 8-23). Mutations in DYT1 gene and in the epsilon-sarcoglycan (SGCE) genes were not detected. We could not find linkage to the dominant DYT6, DYT7, DYT13, or the recessive DYT16 loci. The identification and accurate clinical evaluation of large dystonia families not linked to known genes is crucial for further advancement in molecular genetic characterization of focal dystonia.

The Lancet Neurology, 2020

Background-Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). Although our understanding of the underlying etiologies is incomplete, no large-scale genomic investigation has been performed. We aimed to elucidate the landscape of monogenic causes for the major clinical categories of dystonia. Methods-We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents, recruited between June-1, 2015, and July-31, 2019, from 33 specialty clinical and research centers located in Europe. Affected subjects assessed in this exome-based genetic testing study presented various types of isolated and combined dystonia (with or without coexisting symptoms) including manifestations clinically diagnosed as dystonic cerebral palsy (76/764). Using stringent sequencedata filtering and interpretation protocols, we performed an exome-wide search for causative variants in described disease genes. In the cases that went undiagnosed, candidate dystoniacausing genes were prioritized. Findings-We identified causative or likely causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a significantly higher overall presumptive *

European Journal of Neurology, 2005

Primary dystonia is a movement disorder characterized by involuntary and sustained muscle contractions causing twisting or abnormal postures and mutations in several genes have been identified. Our goal was to investigate, whether the clinical presentation would differ between patients with a positive family history, and patients without. Furthermore, we have performed mutation analysis in the subgroup of patients with a positive family history. A total of 175 patients with primary dystonia were evaluated. Data on gender, presence and frequency of pain and tremor, age of onset, and the distribution of affected body parts were compared between patients with positive and negative family history. All exons of the torsion dystonia 1, GTP cyclohydrolase 1 and ɛ‐sarcoglycan genes were examined in 40 patients by SSCP analysis of PCR products followed by sequencing of variant conformers. Dystonia patients with a positive family history of dystonia had an earlier age of onset and those with ...

Movement Disorders, 2014