Dystonia Family Research Articles

Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights

BackgroundDystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those...

Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions.

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movement-related findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing.

HPCA confirmed as a genetic cause of DYT2‐like dystonia phenotype

HPCA (hippocalcin) is one of the underlying genetic causes of autosomal-recessively inherited forms of dystonia. Here, we describe two consanguineous Turkish DYT-HPCA families carrying the novel HPCA mutations. After detailed clinical and neurological examination, whole-exome sequencing was performed. Whole-exome sequencing analysis revealed two homozygous novel truncating mutations (p.W103* and p.P10PfsTer80) in the HPCA gene in two unrelated Turkish dystonia families presenting with complex dystonia. After identification of HPCA as a genetic cause of DYT-HPCA-like dystonia by Charlesworth et al, this is the second report in the scientific literature that describes dystonia families harboring HPCA mutations. Our findings confirm that HPCA leads to recessively inherited dystonia. © 2018 International Parkinson and Movement Disorder Society.

Low dose olanzapine induced torticollis and treatment: A case report

Olanzapine is a second generation antipsychotic agent that is used for the treatment of the psychotic disorders and mood disorders. Olanzapine is also known to have greater affinity for mezolimbic dopaminergic pathway than for nigrostriyatal dopamine pathway. As a result olanzapine is associated with significantly fewer extrapyramidal symptoms. Tardive dystonia is a rare side effect of antipsychotic treatment frequently causing twisting painful muscle contractions. Effective treatment choice for tardive dystonia is limited. The clinicians must consider acute dystonia neurological disorders and family history for differential diagnosis. Here we present a rare case of torticollis after 5 mg/day olanzapine treatment in a young female patient with psychotic disorder.

Genetic Diagnosis of Two Dopa-Responsive Dystonia Families by Exome Sequencing

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.

DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family.

Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.

No mutations in CIZ1 in twelve adult‐onset primary cervical dystonia families

No mutations in CIZ1 in twelve adult‐onset primary cervical dystonia families

Phenotypic variability in a dystonia family with mutations in the manganese transporter gene

Additional Supporting Information may be found in the online version of this article. Supplementary figure 1. Pedigree of the family studied demonstrating consanguinity, causes and age of death and primary symptoms. Supplementary figure 2. Liver biopsy appearances of patient II-3 at 31 years. Haematoxylin and eosin (H&E), 50x (A). Haematoxylin and eosin (H&E), 100x (B). Periodic acid Schiff reaction (PAS), 100x (C). Liver biopsy showing regenerative nodules and fibrous septa consistent with cirrhosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3

The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

An intragenic duplication in guanosine triphosphate cyclohydrolase‐1 gene in a dopa‐responsive dystonia family

Autosomal dominant dopa-responsive dystonia is commonly caused by mutations in the guanosine triphosphate cyclohydrolase-1 gene. We report a British family that has been followed for more than 20 years in which no mutations were previously identified. Reanalysis of this pedigree detected a duplication of guanosine triphosphate cyclohydrolase-1 exon 2 in affected family members. mRNA analysis showed a mutant transcript with a tandem exon 2 duplication. Four family members developed dopa-responsive dystonia, with onset in their late teens, and subsequently developed restless leg syndrome and migraine. This is the first report of an intragenic guanosine triphosphate cyclohydrolase-1 duplication in a dopa-responsive dystonia family.

Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families

The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early-onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early-onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early-onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor-type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young-onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.

Etiology of musician’s dystonia

To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician's dystonia (MD) and to identify possible environmental triggers. The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH-]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD. A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH- families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members. Our results suggest a genetic contribution to musician's dystonia with phenotypic variability including focal task-specific dystonia.

Molecular analyses of GCH‐1, TH and parkin genes in Chinese dopa‐responsive dystonia families

The symptomatic treatment of dopa-responsive dystonia (DRD) emphasizes the importance of molecular analyses of the GCH-1, TH and parkin genes. However, these analyses have not been extensively studied in Chinese DRD patients. Ten DRD families from the Han ethnic group including 14 patients and 28 clinically unaffected relatives were screened for GCH-1, TH and parkin mutations by direct sequencing, semiquantitative polymerase chain reaction (PCR), polymerase chain reaction-restriction fragment length polymorphism analysis and allele-specific PCR. Variations were verified in 200 unrelated control subjects. We have identified six novel mutations and three known mutations. The novel mutations are Leu91Val, Pro95Leu, Val204Gly and 628delC in GCH-1 gene; Gly216Ser in TH gene; and Cys253Phe in parkin gene. After molecular analyses of seven families with identified GCH-1 mutations, nine asymptomatic cases were found among 23 relatives, which confirmed the low penetrance of DRD. Unlike previous publications, male patients with GCH-1 mutations have early onset ages, while some female patients have very late onset ages in this medium-size series. Our data show that it is difficult to establish an evident genotype-phenotype correlation for DRD. However, it is necessary to know the genetic defects of DRD patients in clinics, which will help elucidate the mode of inheritance, facilitate causal therapy with levodopa and evaluate the prognosis.

Clinical and genetic characterization of a large Dutch family with primary focal dystonia

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.

A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22–q13.12

Primary torsion dystonia is a clinically and genetically heterogeneous group of movement disorders. Fifteen different types of dystonia have been described to date, of whom 14 loci have been mapped, but only seven genes identified. Several different modes of inheritance have been described, including autosomal dominant transmission with reduced penetrance (12 loci), recessive X-linked (one locus), and autosomal recessive transmission (three loci). In this study, we describe the localization of a novel form of autosomal recessive, primary focal torsion dystonia using a genomewide search in a large consanguineous Lebanese family with three affected individuals. Homozygosity mapping with 382 microsatellite markers was conducted. Linkage analysis and haplotype construction allowed us to identify a novel locus designated as DYT17, within a 20.5-Mb interval on chromosome 20. Of the 270 known genes spread on this interval, 27 candidate genes were tested and excluded as responsible for the disease. Fine mapping by identification of other dystonia families linked to chromosome 20 and sequencing of candidate genes in the refined interval is required in order to identify the causative gene in DYT17.

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.

We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.

Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities.

The discovery of endogenous bioactive peptides has typically required a lengthy identification process. Computer-assisted analysis of cDNA and genomic DNA sequence information can markedly shorten the process. A bioinformatic analysis of full-length, enriched human cDNA libraries searching for previously unidentified bioactive peptides resulted in the identification and characterization of two related peptides of 28 and 20 amino acids, which we designated salusin-alpha and salusin-beta. Salusins are translated from an alternatively spliced mRNA of TOR2A, a gene encoding a protein of the torsion dystonia family. Intravenous administration of salusin-alpha or salusin-beta to rats causes rapid, profound hypotension and bradycardia. Salusins increase intracellular Ca2+, upregulate a variety of genes and induce cell mitogenesis. Salusin-beta stimulates the release of arginine-vasopressin from rat pituitary. Expression of TOR2A mRNA and its splicing into preprosalusin are ubiquitous, and immunoreactive salusin-alpha and salusin-beta are detected in many human tissues, plasma and urine, suggesting that salusins are endocrine and/or paracrine factors.

Neurological disorders in members of families with Leber's hereditary optic neuropathy (LHON) caused by different mitochondrial mutations.

Neurological abnormalities have been occasionally associated with Leber's hereditary optic neuropathy (LHON). We describe four patients with spastic dystonia from two of our 35 LHON families. Magnetic resonance imaging revealed signal alterations of globus pallidus, putamen, internal capsula, and substantia nigra. Neuropathological findings in one of the patients with dystonia are described. Each of the dystonia families carries a different mtDNA mutation; one at np 3460 and one at np 11778. Periventricular multiple sclerosis-like white matter lesions were observed in one individual from a third family with the mtDNA 3460 mutation. Neurological disorders are probably underestimated in association with LHON.