Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date, at least 12 types of primary dystonia can be distinguished on a genetic basis. A 3-bp deletion in the DYT1 gene causes early onset, generalized torsion dystonia (TD), and mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes result in dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor in one large family (DYT11) has recently been implicated in myoclonus-dystonia. Furthermore, seven other loci for dystonia genes have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), three types of paroxysmal dystonia (DYT8-10), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia-parkinsonism (DYT12). No positive linkage results have yet been obtained for autosomal recessive TD (DYT2) and several other families of different types of dominantly inherited TD (DYT4). In addition, hereditary secondary dystonia may occur as part of familial diseases of the basal ganglia, metabolic and storage disorders, and various X-linked and other familial neurodegenerative syndromes affecting the basal ganglia. It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.
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PMID:[Genetics of dystonia]. 1091 37

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.
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PMID:Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. 1152 94

Mutations in the gene for epsilon sarcoglycan (epsilon-SG) are associated with a disorder of the central nervous system, the myoclonus-dystonia syndrome (MDS; DYT11). In contrast, mutations of other sarcoglycan family members lead to limb-girdle muscular dystrophies. To establish the framework for functional studies of epsilon-SG, we cloned rat epsilon-SG cDNA, quantified epsilon-SG mRNA levels in neural and non-neural tissues at different developmental time points with relative quantitative multiplex real-time reverse transcriptase PCR (RT-PCR), and characterized the distribution of epsilon-SG mRNA in brain with in situ hybridization. Rat epsilon-SG cDNA contains an open reading frame (ORF) of 1311 bp that encodes a 437-amino acid (aa) protein with 95.9% and 98.2% identity to human and mouse epsilon-SG amino acid sequences, respectively. Using real-time RT-PCR, epsilon-SG was detected in both neural (cerebellar cortex, striatum, cerebral cortex, thalamus, hippocampus) and non-neural (muscle, liver, kidney, heart) tissues at each developmental time point tested [Embryonic Day 20 (E20), Postnatal Day 1 (P1), P7, P14, P36, 6 months, 1.5 years). Levels of epsilon-SG mRNA were highest at E20 in all tissues. The developmental regulation of epsilon-SG mRNA expression was most striking in muscle with E20 and early postnatal epsilon-SG mRNA levels over 10 times higher than those seen in adult rats. In adult rats, epsilon-SG mRNA levels were several-fold higher in brain, particularly cerebellar cortex, than in muscle. Radioactive in situ hybridization showed that epsilon-SG mRNA was widely distributed in rat brain. Robust hybridization signal was obtained from regions with dense neuronal packing such as the hippocampus, cerebellar molecular layer, and cerebral cortex. Our results suggest that epsilon-SG participates in the development of both neural and non-neural tissues and contributes to neuronal structure in the adult central nervous system.
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PMID:Cloning, developmental regulation and neural localization of rat epsilon-sarcoglycan. 1462 80

The pathophysiology of Myoclonus-Dystonia (M-D), an autosomal dominantly inherited movement disorder is largely unknown. In different forms of dystonia abnormal intermuscular coherence is present. The objective of this study was to investigate whether the myoclonic and dystonic features are the result of an abnormal common drive to the muscles in M-D. Coherence analysis was performed in 20 DYT11 mutation carriers (MC) and 13 healthy controls during resting condition and during weak isometric contraction of the arm and neck. The EMG-EMG coherence analysis showed significantly increased intermuscular 3 to 10 Hz coherence in 4 DYT11 MC with clinical pronounced (mobile and static) dystonia. This coherence was not present in DYT11 MC with mild (static) dystonia and/or predominating myoclonus. The EEG-EMG analysis showed significant 15 to 30 Hz coherence during weak isometric contraction of the arm in five healthy controls, but in none of the DYT11 MC. The intermuscular coherence in the low frequency band in DYT11 MC with predominant dystonia is concordant with the previously described coherence in dystonia and suggests that the pathophysiology of M-D shares common pathophysiological features with dystonia. The absence of 15 to 30 Hz EEG-EMG coherence in DYT11 MC may reflect abnormal motor activation caused by an altered cortical drive because of the basal ganglia dysfunction.
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PMID:Abnormal low frequency drive in myoclonus-dystonia patients correlates with presence of dystonia. 1748 90

Because of clinical similarities, benign hereditary chorea and myoclonus-dystonia (DYT11) might be confused. No systematic comparisons of genetically proven cases with thyroid transcription factor-1 (TITF-1) and epsilon-sarcoglycan (SGCE) mutations have been performed to date. Three index patients and one index patients' daughter underwent genetic analysis of the TITF-1 and the SGCE gene. The movement disorders of all patients were assessed by video review. A new splicing mutation (376-2A>C) of the TITF-1 gene was detected in a mother and her daughter. Two additional patients carried a de novo SGCE nonsense mutation in exon 3 (R97X) and a novel SGCE missense mutation in exon 6 (G227V). Both TITF-1 mutation carriers presented with infancy-onset, nonprogressive chorea, which responded to alcohol intake. In addition, dystonia of the neck and trunk as well as fleeting jerky movements of the distal limbs could be observed. The mutually exclusive appearance of lightning-like myoclonic jerks triggered by action in SGCE mutation carriers and of continuous chorea of all limbs in TITF-1 mutation carriers phenotypically discriminated both genetic disorders. TITF-1 mutations should be considered in choreiform movement disorders with onset in infancy even in the presence of dystonia and myoclonic jerks.
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PMID:Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. 1770 43

Myoclonus-dystonia (M-D, DYT11) is a dystonia plus syndrome characterized by brief myoclonic jerks predominantly of neck and upper limbs in combination with focal or segmental dystonia. It is caused by heterozygous mutations of the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21.3. We present three patients with heterozygous large deletions in the 7q21.13-21.3 region. By quantitative analysis of single nucleotide polymorphism (SNP) oligonucleotide arrays, the deletion size was determined to range from 1.63 to 8.78 Mb. All deletions contained the maternally imprinted SGCE gene and up to 43 additional neighbouring genes. Two of the patients presented with typical M-D, whereas one paediatric patient with split-hand/split-foot malformation and sensorineural hearing loss (SHFM1D, OMIM 220600) had not developed M-D at the age of 9 years. This patient had the largest deletion of 8.78 Mb (7q21.13-21.3) containing also SHFM1, DLX6 and DLX5, which had been previously shown to be deleted in SHFM1D. In two patients, the deletions removed the paternal allele of the KRIT1 gene, which is a major cause of cavernous cerebral malformations type 1 (CCM1). Only the adult patient showed asymptomatic cavernous cerebral malformations on cranial MRI, underlining age-dependent penetrance and haploinsufficiency as pivotal features of patients with KRIT1 mutations. All three deletions contained the COL1A2 gene. In contrast to dominant negative point mutations, which cause osteogenesis imperfecta with bone fractures, haploinsufficiency of COL1A2 resulted only in subtle symptoms like recurrent joint subluxation or hypodontia. Assessing copy number variations by SNP arrays is an easy and reliable technique to delineate the size of human interstitial deletions. It will therefore become a standard technique to study patients, in whom heterozygous whole gene deletions are detected and information on neighbouring deleted genes is required for comprehensive genetic counselling and clinical management.
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PMID:Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype. 1789 12

Myoclonus-dystonia (M-D) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (DYT11). We explore pathophysiological characteristics of M-D with the hypothesis that they may be different from those of sporadic or genetic dystonia. We compared five carriers of the DYT11 gene mutation and 10 healthy controls. Using transcranial magnetic stimulation, we measured parameters assessing cortical membrane excitability (active motor threshold, aMT) and synaptic activity (short interval, sICI) and afferent (AI) intracortical inhibitions and their interaction. aMT was significantly higher in the DYT11 gene carriers than in normal subjects. The others parameters (sICI, AI and their interaction) were not different between the two groups. In DYT11 gene carriers cortical membrane excitability was impaired while parameters assessing cortical synaptic activity were normal. Opposite results have been obtained in focal sporadic and generalized DYT1 dystonias.
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PMID:Cortical excitability in DYT-11 positive myoclonus dystonia. 1826 16

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder with myoclonic jerks and dystonic contractions most frequently due to a mutation in the epsilon-sarcoglycan (SGCE, DYT11) gene. We describe two unrelated children with M-D (DYT11) who presented with writer's cramp. Due to maternal imprinting the family history appeared initially negative for M-D. In children with writer's cramp screening of the SGCE gene should be considered, even with a negative family history.
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PMID:Pediatric writer's cramp in myoclonus-dystonia: maternal imprinting hides positive family history. 1857 46

Inherited myoclonus dystonia (M-D, DYT11) is an autosomal dominant dystonia-plus syndrome, which in many families is caused by mutations in the SGCE/(epsilon-sarcoglycan gene. We present a family with M-D, with an unusual presentation characterized by infantile onset with falls in two sisters and adult-onset writer's cramp in their father. Myoclonus dystonia is typically characterized by a variable mixture of alcohol-sensitive myoclonic jerks and dystonia classically affecting mainly the proximal arms and neck. Leg involvement is less frequent, and to our knowledge, initial presentation with falls has not previously been described. The unusual phenotype of the family is discussed.
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PMID:Unusual familial presentation of epsilon-sarcoglycan gene mutation with falls and writer's cramp. 1870 14

Mutations in the epsilon-sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus-dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11-MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 +/- 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo-rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a "startle-like" muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long-loop reflexes were normal, as was silent period and long-term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short-term intracortical inhibition revealed subtle impairment, and event-related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11-MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11-MDS may justify the involvement of different brain areas.
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PMID:A neurophysiological study of myoclonus in patients with DYT11 myoclonus-dystonia syndrome. 1875 36


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