Deborah Raymond

The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen independently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

The DYT1 phenotype and guidelines for diagnostic testing

Objective: To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1 deletion carriers. Methods: The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients. Results: The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease. Conclusions: Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.

Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia

We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary torsion dystonia (also known as DYT6 dystonia). Another mutation in a German family with primary torsion dystonia suggests that THAP1 mutations also cause dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 dystonia.

Mutations in GNAL cause primary torsion dystonia

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.

Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study

BACKGROUND Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. METHODS We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed. FINDINGS Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found. INTERPRETATION Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. FUNDING Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.

Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence.

Background: Inherited myoclonus–dystonia (M-D) is a disorder that is characterized primarily by myoclonic jerks and is often accompanied by dystonia. In addition to motor features, psychiatric disease is reported in some families. Methods: To determine whether the same genetic etiology underlies both neurologic and psychiatric signs, the authors studied psychiatric symptoms in nonmanifesting carriers (NMC), noncarriers (NC), and manifesting carriers (MC) in three families demonstrating linkage of M-D to the 7q21 locus. Interviewers administered the computerized version of the Composite International Diagnostic Interview. Algorithms for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of obsessive–compulsive disorder (OCD), generalized anxiety disorder, major affective disorder, alcohol abuse, alcohol dependence, drug abuse, and drug dependence were used. Rates of disorders among the MC, NMC, and NC were compared. Results: Of 55 participating individuals, 16 were MC, 11 were NMC, and 28 were NC. The rate of OCD was greater in carriers (5/27) compared with NC (0/28) (p = 0.023). It was also greater in the symptomatic gene carriers (4/16) compared with the asymptomatic group (1/11) (p = 0.022). Alcohol dependence was increased in the symptomatic carriers (7/16) (p = 0.027), but not in the carrier group overall (7/27). Conclusion: OCD may be associated with the DYT11 M-D gene; however, a larger sample is necessary to confirm this finding. Alcohol dependence is highly associated with expressing symptoms of M-D. This may be explained by self-medication with alcohol to improve motor symptoms of M-D.

Primary dystonia: Is abnormal functional brain architecture linked to genotype?

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.

Regional metabolism in primary torsion dystonia: effects of penetrance and genotype.

Background: The authors have previously used [18F]fluorodeoxyglucose (FDG) PET to identify a reproducible pattern of regional glucose metabolism that was expressed in both manifesting and nonmanifesting carriers of the DYT1 primary dystonia mutation. Objective: To identify specific regions that discriminated subjects according to clinical penetrance and genotype. Methods: FDG PET was used to scan 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers, as well as 11 control subjects. The data from all five groups were analyzed with statistical parametric mapping and analysis of variance with posthoc contrasts. Results: A dissociation of metabolic changes was found related to phenotype and genotype. Manifesting gene carriers of both genotypes exhibited bilateral hypermetabolism in the presupplementary motor area (Brodmann area [BA] 6) and parietal association cortices (BA 40/7) compared with the respective nonmanifesting counterparts. By contrast, genotype-specific increases in metabolism were found in the putamen, anterior cingulate (BA 24/32), and cerebellar hemispheres of DYT1 carriers. Genotype-specific changes in DYT6 involved hypometabolism of the putamen and hypermetabolism in the temporal cortex (BA 21). Conclusions: Dystonia may be associated with abnormal movement preparation caused by defective sensorimotor integration. Whereas clinical manifestations are related to cortical dysfunction, metabolic abnormalities in subcortical structures may represent trait features that are specific for individual dystonia genotypes.

Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31

Essential myoclonus‐dystonia is a neurological condition characterized by myoclonic and dystonic muscle contractions and the absence of other neurological signs or laboratory abnormalities; it is often responsive to alcohol. The disorder may be familial with apparent autosomal dominant inheritance. We report a large kindred with essential familial myoclonus‐dystonia and map a locus for the disorder to a 28‐cM region of chromosome 7q21‐q31.

Phenotypic features of myoclonus-dystonia in three kindreds

Background Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the &egr;-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2) gene (one family). Objective To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. Methods Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. Results Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. Conclusions Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.