Familial Dystonia Research Articles

Familial myoclonic dystonia type 11 with deep neurostimulator placement in bilateral internal globus pallidus. Case report and literature review

Familial myoclonic dystonia type 11 with deep neurostimulator placement in bilateral internal globus pallidus. Case report and literature review

Whole exome sequencing of familial, combined or complex dystonia

Whole exome sequencing of familial, combined or complex dystonia

A new mutation in the GNAL gene in familial dystonia presenting with mental symptoms

A new mutation in the GNAL gene in familial dystonia presenting with mental symptoms

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.

KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia.

Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia.

Increased diagnostic yield in complex dystonia through exome sequencing

IntroductionA strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing. Material and methodsWES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature. ResultsWe identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%–5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%–16.7%; p < 0.002). ConclusionOur approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.

Dystonia: Then and now

IntroductionDystonia is a rare disorder that has undergone extensive scientific investigation leading to a transformation of understanding over the past century. MethodsThis manuscript was prepared through a review of relevant literature for each topic. ResultsHistorically dystonia was considered the manifestation of psychiatric disorders. Subsequently, investigations have firmly established this as a neurological disorder. Though electrophysiological and imaging, dystonia is thought to arise from a loss inhibition of motor programs, defective sensorimotor integration and abnormal plasticity. The genetic studies in dystonia have revealed the hereditary nature of many forms of familial dystonia. Treatment of dystonia has focused primarily on botulinum toxin for focal and segmental dystonia and deep brain stimulation of the globus pallidus interna for generalized and medically refractory focal dystonia. ConclusionThe progress in dystonia in the past century has revised the concepts of this disorder, increased knowledge of genetics and underlying pathophysiology, and provides new therapeutic targets. To promote future research the development of diagnostic criteria, biomarkers and validated rating scales for each form of dystonia is essential.

Comparison study of gut microbiota in case of Parkinson’s disease and other neurological disorders

Currently the role of microbiota in diseases pathogenesis, its therapeutic and diagnostic potential are of the utmost interest for scientists and medical doctors. Parkinson’s disease is neurodegenerative disorder for which microbiota’s dysbiosis was previously shown. The main goal of the study is to compare the colon microbiota composition in case of Parkinson’s disease and other neurological pathologies, including idiopathic familial dystonia, essential tremor, multiple sclerosis, multiple system atrophy in order to determine the intestinal flora landscape specific to Parkinson’s disease. Material and methods. One hundred twenty-six patients, 93 with Parkinson’s disease and 33 with other neurological pathology were examined. For all patients, physical examination and fecal samples collection were performed. Microbiota taxonomic composition was analyzed by sequencing of bacterial 16S rRNA genes followed by bioinformatic and statistical analysis. As a result of the study, significant differences between groups in microbiota composition were found. Gut microbiota of patients with Parkinson’s disease was characterized by increase of Desulfovibrio piger, Lactobacillus mucosae, Yokenella regensburgei, Alistipes indistinctus, Oscillospira capillosus, Clostridium bolteae, Soleaferrea massiliensis, Butyricimonas virosa, Dorea massiliensis, Victivallis vadensis abundances. Patients with other neurological diseases had increased levels of bacteria belonging to Blautia, Intestinibacter, Coprococcus genera and Anoxystipes fissicatena, Fusobacterium periodonticum, Gemmiger formicilis, Papillibacter cinnamivorans, Roseburia faecis, Lachnoclostridium indolis, Clostridium populeti, Clostridium tertium, Roseburia intestinalis, Eubacterium desmolans, Eubacterium cylindroides, Clostridium clariflavum, Eubacterium eligens, Coprococcus eutactus, Intestinibacter bartlettii species in their gut microbiota. Consequently, gut microbiota in case of Parkinson’s disease was different from the microbiota of patients with other neurological diseases, including neuroinflammatory and neurodegenerative disorders, in terms of taxonomic diversity and composition.

Familial dystonia with cerebral calcification: case report and genetic update

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Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene.

We identified three novel mutations of the GTP cyclohydrolase 1 (GCH1) gene in patients with familial dopa-responsive dystonia (DRD), but were unable to identify meaningful sporadic mutations in patients with no obvious family DRD background. To investigate whether GCH1 regional deletions account for the etiology of DRD, we screened for heterozygous exonic deletions in DRD families and in patients with sporadic DRD. Multiple ligation-dependent probe amplification analysis and quantitative real-time polymerase chain reaction amplification was performed in all members of our DRD cohort and in controls to detect exonic deletions in GCH1, tyrosine hydroxylase, and the epsilon-sarcoglycan-encoding (SGCE) genes. Using these techniques, we detected a GCH1 exon 1 heterozygous deletion in 1 of 10 patients with sporadic DRD. Therefore, we concluded that exonic deletion in the GCH1 gene only accounted for the etiology in a small percentage of patients with sporadic DRD in our Han Chinese cohort.

Genetic evaluation for TOR1-A (DYT1) in Brazilian patients with dystonia

Several genes have been mapped in families or in sporadic cases of dystonia. TOR1-A (DYT1) gene was linked to isolated dystonia. To associate clinical information of patients with dystonia with the TOR1-A gene mutations. Eighty-eight patients with dystonia in cervical area (focal, segmental, multifocal and generalized) were recruited at Movement Disorders Clinic of Hospital de Clínicas of the Federal University of Paraná between June of 2008 and June of 2009. They were submitted to the clinical evaluation. DNA was extract from blood and submitted at analysis to TOR1-A mutations by PCR according standard protocols. Two patients had c.907GAGdel mutation on TOR1-A gene. These patients, with familial history of dystonia, started his symptoms by legs and had secondary generalization. We can suggest that analysis for TOR1-A mutations should be performed only in patients with early onset, generalized and familial dystonia.

The phenotypic spectrum of DYT24 due to ANO3 mutations

Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 The Authors. Movement Disorders published by International Parkinson and Movement Disorder Society

No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia

Recently, using a whole exome sequencing approach, mutations in GNAL were identified as a novel cause of primary dystonia by one group[1] and subsequently confirmed by another.[2] Mutations in this gene appear to cause autosomal dominant, primary dystonia with a cervical predilection and evidence of incomplete penetrance.[1] The initial discovery paper by Fuchs et al reported GNAL mutations in 6 out of 39 families screened (~15%). However, in the subsequent study by Vemula et al, only 3 GNAL mutations were detected in 760 subjects with familial or sporadic primary dystonia (<0.5%). An accurate estimate of the prevalence of GNAL mutations is important as a mutation frequency of ~15% would justify early and widespread genetic testing of GNAL in familial dystonia, whereas a frequency of <0.5% would not. We screened GNAL by Sanger sequencing using the DNA samples from 192 probands (136 female and 56 male) with either familial or sporadic cervical dystonia, selected from a library of research samples on the basis of a clinical description of focal or segmental dystonia that included the cervical region. Local ethics committee approval was obtained for the study. A family history, defined as one or more first or second-degree relatives with dystonia, was recorded in 84 cases. Tremor was recorded in 53 cases. All familial cases had been screened for TOR1A, THAP1 and ANO3 mutations and were negative. Primers were designed to amplify all exons, the exon/intron boundaries and the 5′UTRs of both major isoforms of GNAL (ENS0334049 and ENS0423027). We identified only two novel single nucleotide variations in GNAL in three individuals in our case cohort. The first was a missense mutation in exon 2 of the gene (cDNA.1053C>T; P149S in ENS0334049) that was detected in one individual with onset of cervical dystonia in the 4th decade, with a similarly affected father, suggesting autosomal dominant inheritance. However, segregation analysis revealed the variant had in fact been inherited from his unaffected mother and was also present in his unaffected brother (see Fig. 1A), ruling it out as the cause of the dystonia in this family. The second variant, located in the 5′UTR of isoform 2 (cDNA.199C>T in ENS0423027), was found in two individuals in our cohort exhibiting onset of cervical dystonia in the 6th decade. One individual was a sporadic case whereas the other was part of family with multiple affected members (see Fig.1B-C). Despite affecting a highly conserved base (PhyloP score = 4.158), the variant failed to segregate with disease in the family, being absent in two affected individuals (see Fig. 1C). Figure 1 Family trees for individuals with novel variants in GNAL. In summary, we did not identify any mutations in GNAL that could be a cause of the dystonia in 192 cases drawn from the United Kingdom, including 84 familial cases. Our own data suggest that GNAL mutations do not represent a common cause of dystonia — in the U.K. population at least — and that the overall frequency of GNAL mutations may be closer to the figure obtained by Vemula et al[2] than the 15% initially reported by Fuchs et al.[1] This study also emphasises the importance of segregation analysis in establishing the pathogenicity or otherwise of novel variants and suggests that other novel genetic causes of dystonia remain to be identified.

Emerging common molecular pathways for primary dystonia

The dystonias are a group of hyperkinetic movement disorders whose principal cause is neuron dysfunction at 1 or more interconnected nodes of the motor system. The study of genes and proteins that cause familial dystonia provides critical information about the cellular pathways involved in this dysfunction, which disrupts the motor pathways at the systems level. In recent years study of the increasing number of DYT genes has implicated a number of cell functions that appear to be involved in the pathogenesis of dystonia. A review of the literature published in English-language publications available on PubMed relating to the genetics and cellular pathology of dystonia was performed. Numerous potential pathogenetic mechanisms have been identified. We describe those that fall into 3 emerging thematic groups: cell-cycle and transcriptional regulation in the nucleus, endoplasmic reticulum and nuclear envelope function, and control of synaptic function. © 2013 Movement Disorder Society.

GTP Cyclohydrolase I and Tyrosine Hydroxylase Gene Mutations in Familial and Sporadic Dopa-Responsive Dystonia Patients

Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases. We used PCR to sequence all exons and splicing sites of the GCH1 and TH genes. Three novel heterozygous GCH1 mutations (Tyr75Cys, Ala98Val, and Ile135Thr) were identified in three DRD pedigrees. We failed to identify any GCH1 or TH mutation in two affected sisters. Three symptom-free male GCH1 mutation carriers were found in two DRD pedigrees. For those DRD siblings that shared the same GCH1 mutation, symptoms and age of onset varied. In 10 sporadic cases, only two heterozygous TH mutations (Ser19Cys and Gly397Arg) were found in two subjects with unknown pathogenicity. No GCH1 and TH mutation was found in 40 unrelated normal Han Chinese controls. GCH1 mutation is the main etiology of familial DRD. Three novel GCH1 mutations were identified in this study. Genetic heterogeneity and incomplete penetrance were quite common in DRD patients, especially in sporadic cases. Genetic screening may help establish the diagnosis of DRD; however, a negative GCH1 and TH mutation test would not exclude the diagnosis.

Is TOR1A a risk factor in adult‐onset primary torsion dystonia?

Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case-control TOR1A association studies in adult-onset primary torsion dystonia. In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases.

Role of Gα(olf) in familial and sporadic adult-onset primary dystonia

The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.

Phenotypes and genetic architecture of focal primary torsion dystonia

BackgroundThe focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants...

Aspects cliniques et thérapeutiques des dystonies en Tunisie : étude prospective sur cinq ans

IntroductionStudies of dystonia are heterogeneous and there are no studies on this disease in Tunisia. The aim of our study was to determine the frequency of dystonia in the hospital population, to identify different forms of dystonia according to age of onset, distribution, to determine etiologies and to describe treatment. MethodsWe conducted a prospective study over a 5-year period (from January 2005 to November 2009) including all patients diagnosed with dystonia and followed at the Child and Adolescent Neurology Department and “Movement Disorders and Botulinum Toxin” consultation of the National Institute of Neurology of Tunis. ResultsTwo hundred patients were included (2.2% of our patients). Mean age was 26.4±21.4 years and sex ratio H:F 1.3. Consanguinity rate was 29%. Main features of dystonia were action dystonia (78.5%), generalized forms (47%) and secondary forms (58%). A pyramidal syndrome and other movement disorders were the most common signs associated with dystonia (36.5% and 33.5% respectively). In the group of secondary dystonia, mains etiologies were dystonia due to exogenic agent (56%), neuro-metabolic diseases (26%), hereditary degenerative disease (13%) and psychogenic dystonia (5%). Dystonia was primary in 44% (84 patients). Different treatments were used and a dramatic improvement in some patients was noted with levodopa and botulinum toxin injections. A multidisciplinary approach associated with medical treatment led to recovery or improved prognosis. Discussion and conclusionVery few studies have been devoted to reporting a large series of dystonic patients. Our study is the first to describe both primary and secondary dystonia in 200 Tunisian patients. The presence of familial dystonia in our country suggests a genetic origin. Further work including genetic analysis with a screening of known mutations responsible for dystonia and the informative families with unknown mutations would be useful. Specific studies designed to identify new genes causal in dystonia are needed.