RESUMO
Advances in the genetics of dystonia have further elucidated the pathophysiology of this clinically and etiologically heterogeneous group of movement disorders. Currently, 20 monogenic forms of dystonia, designated by the acronym DYT, are grouped as 1) pure dystonias, 2) dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes and loci, including the 1) detection of two primary dystonia genes (DYT6, DYT16), 2) identification of the DYT17 locus, 3) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 (glucose transporter of the blood-brain barrier) deficiency syndrome (DYT18), 4) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, and 5) redefinition of DYT14 as DYT5. Further, we review current knowledge regarding genetic modifiers and susceptibility factors. Because recognizing and diagnosing monogenic dystonias have important implications for patients and their families with regard to counseling, prognosis, and treatment, we highlight clinical "red flags" of individual subtypes and review guidelines for genetic testing.
Assuntos
Proteínas de Transporte/genética , Distonia Muscular Deformante/etiologia , Distonia Muscular Deformante/genética , Predisposição Genética para Doença , Proteínas de Transporte/classificação , Distonia Muscular Deformante/classificação , Testes Genéticos , Humanos , Mutação/genéticaRESUMO
DYT1 dystonia is an autosomal dominant movement disorder, characterized by early onset of involuntary sustained muscle contractions. It is caused by a 3-bp deletion in the DYT1 gene, which results in the deletion of a single glutamate residue in the C-terminus of the protein TA (torsinA). TA is a member of the AAA+ (ATPase associated with various cellular activities) family of chaperones with multiple functions in the cell. There is no evidence of neurodegeneration in DYT1 dystonia, which suggests that mutant TA leads to functional neuronal abnormalities, leading to dystonic movements. In recent years, different functional roles have been attributed to TA, including being a component of the cytoskeleton and the NE (nuclear envelope), and involvement in the secretory pathway and SV (synaptic vesicle) machinery. The aim of the present review is to summarize these findings and the different models proposed, which have contributed to our current understanding of the function of TA, and also to discuss the evidence implicating TA in SV function.
Assuntos
Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Sinapses/patologia , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/patologia , Distúrbios Distônicos/classificação , Distúrbios Distônicos/genética , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/fisiologia , Conformação Molecular , Proteínas Mutantes/fisiologia , Ligação Proteica , Relação Estrutura-Atividade , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/patologia , Vesículas Sinápticas/fisiologia , Distribuição TecidualRESUMO
INTRODUCTION: Deep brain stimulation (DBS) at the internal globus pallidus (GPi) is an effective treatment for some patients with medically refractory torsion dystonia. In this article, we review the results of pallidal DBS surgery in children with dystonia. Details of the DBS procedure and programming of the DBS devices are discussed. DISCUSSION: Pallidal DBS is most effective in patients with primary generalized dystonia. Children and adolescents possessing the DYT1 gene mutation may respond best of all. The presence of static dystonic postures and/or fixed orthopedic contractures may limit the functional response to DBS and may require additional surgery. CONCLUSION: As a group, patients with secondary dystonias respond less well to DBS than patients with primary dystonia. However, patients with dystonia secondary to anoxic brain injury who have grossly intact basal ganglia anatomy may represent a subpopulation for whom pallidal DBS is a viable option.
Assuntos
Estimulação Encefálica Profunda/métodos , Distonia Muscular Deformante/terapia , Pediatria , Avaliação da Deficiência , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/patologia , Humanos , Índice de Gravidade de DoençaRESUMO
Dystonias are a heterogeneous group of neurological disorders. In this paper we present clinical and molecular characteristics of inherited primary torsion dystonias. Clinical data and current concepts on the pathogenesis of dystonias with known molecular defect are presented in detail. Therapeutic options in patients with primary dystonias are also discussed.
Assuntos
Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/genética , Adolescente , Idade de Início , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Distonia Muscular Deformante/terapia , Marcadores Genéticos/genética , Humanos , Lactente , Mutação/genéticaRESUMO
Dystonia is a syndrome which is characterized by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. According to genetic basis, dystonia is classified into 13 subtypes. We mainly discussed two subtypes, DYT1 and DYT5, in this review. Early-onset primary dystonia is caused by the mutation of DYT1 gene, which leads to TORSINA abnormal. GTP cyclohydrolase 1 (GTPCH1)-deficient DRD (DYT5) is caused by the mutations of GCH1 gene. By genetic testing, we can confirm clinical diagnosis of each subtype and develop prenatal diagnosis for it.
Assuntos
Distonia Muscular Deformante/diagnóstico , Distonia Muscular Deformante/genética , Distonia Muscular Deformante/classificação , HumanosAssuntos
Proteínas de Transporte/genética , Distonia Muscular Deformante/genética , Distúrbios Distônicos/genética , Idade de Início , Mapeamento Cromossômico , Cromossomos , Distonia Muscular Deformante/classificação , Distúrbios Distônicos/classificação , Ligação Genética , Genótipo , Humanos , Escore Lod , Mutação , Doença de Parkinson/genética , FenótipoAssuntos
Idade de Início , Proteínas de Transporte/genética , Distonia Muscular Deformante/epidemiologia , Distúrbios Distônicos/epidemiologia , Chaperonas Moleculares , Adulto , Idoso , Envelhecimento , Análise Mutacional de DNA , Progressão da Doença , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/genética , Distonia Muscular Deformante/fisiopatologia , Distúrbios Distônicos/classificação , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Feminino , Testes Genéticos/métodos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Exame Neurológico/métodos , Linhagem , FenótipoRESUMO
The authors report the clinical characteristics of a Sephardic Jewish kindred with autosomal recessive DYT2-like primary torsion dystonia. Three siblings had childhood onset of limb dystonia, and slow progression to generalized dystonia with predominant cranio-cervical involvement. There were no other abnormal signs, apart from dystonia and jerky tremor over a 12-year follow-up. All investigations for other causes of primary and secondary dystonia had normal results.
Assuntos
Distonia Muscular Deformante/diagnóstico , Distonia Muscular Deformante/genética , Chaperonas Moleculares , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Consanguinidade , Progressão da Doença , Distonia Muscular Deformante/classificação , Família , Feminino , Genes Recessivos , Humanos , Lactente , Irã (Geográfico)/etnologia , Judeus/etnologia , Judeus/genética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , LinhagemRESUMO
We evaluated the prevalence of focal dystonias in the western area of Tottori Prefecture in Japan. The population of the area was 244,935 on October 1, 1992. Because four patients with blepharospasm and three patients with writer's cramp did not visit any hospitals or clinics in 1993 and did not reply to our question letter, we could not confirm their present condition: with or without focal dystonia in 1993. Four patients with facial dystonia including blepharospasm and oromandibular dystonia, seven with spasmodic torticollis, and four with writer's cramp were observed. The prevalence of focal dystonias was 6.12 per 100,000 persons, which may be lower than that in western countries. Although the reasons for this difference are still unclear, a genetic factor may be one implication.
Assuntos
Comparação Transcultural , Distonia Muscular Deformante/epidemiologia , Adulto , Idoso , Blefarospasmo/classificação , Blefarospasmo/diagnóstico , Blefarospasmo/epidemiologia , Estudos Transversais , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/diagnóstico , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Síndrome de Meige/classificação , Síndrome de Meige/diagnóstico , Síndrome de Meige/epidemiologia , Pessoa de Meia-Idade , Cãibra Muscular/classificação , Cãibra Muscular/diagnóstico , Cãibra Muscular/epidemiologia , Torcicolo/classificação , Torcicolo/diagnóstico , Torcicolo/epidemiologiaRESUMO
Twenty-two cases with spastic torticollis in children are analyzed. This syndrome was the only suffering in ten children and was a component of generalized forms of deforming muscular dystonia in twelve. In such cases the time course of spastic torticollis clinical picture, possible alteration of tonic and clinical forms, involvement as a rule of hands and shoulders muscles permit regarding this condition as a variant of local deforming muscular dystonia and not an individual hyperkinesis. The efficacy of routine drug therapy administered to these patients directly depended on the form and pattern of spastic torticollis. Positive shifts were observed in 90.9% of patients, in 40.9% a marked positive effect was attained.
Assuntos
Torcicolo/diagnóstico , Adolescente , Criança , Doença Crônica , Terapia Combinada , Quimioterapia Combinada , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/diagnóstico , Distonia Muscular Deformante/terapia , Feminino , Humanos , Masculino , Espasticidade Muscular/classificação , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/terapia , Indução de Remissão , Torcicolo/classificação , Torcicolo/terapiaRESUMO
Thirty-eight children with deforming muscular dystonia were treated. Eighteen of them suffered from rigid, seven from hyperkinetic, and 13 from, mixed forms of the disease. To patients with rigid condition DOPA-containing drugs (nakom) were administered in combination with cholinolytics, diphenin, midocalm. If the condition proved resistant to therapy, parlodel, remantadin, antidepressants were added. To patients with hyperkinetic forms haloperidol, clonazepam, dephenin, finlepsin were administered. In mixed forms combinations of nakom with haloperidol and clonazepam were prescribed. The best results were attained in therapy of rigid forms (77% of all rigid forms), particularly of DOPA-dependent forms and those with local involvement.
Assuntos
Distonia Muscular Deformante/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Dopaminérgicos/uso terapêutico , Antagonistas de Dopamina , Quimioterapia Combinada , Distonia Muscular Deformante/classificação , Humanos , Hipercinese/tratamento farmacológico , Rigidez Muscular/tratamento farmacológico , Indução de RemissãoRESUMO
Dystonia is a term used to describe a specific set of abnormal movements that can occur as a symptom of a variety of neurologic disorders, but also as a disease entity in its own right. This review focuses on the primary dystonias and delineates the genetic contribution to these disorders. Included is a description of the well recognized forms of primary dystonias which manifest autosomal dominant inheritance, especially the "classic" type of early onset, generalized torsion dystonia, but also other clinically distinct forms such as myoclonic dystonia, paroxysmal dystonia, and DOPA-responsive dystonia. Also, a summary of the molecular genetic studies pertinent to these disorders and a discussion of the implications of recent genetic research for delineating the wide spectrum of this phenotypically and genetically heterogeneous group of diseases are forthcoming.
Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Distonia/genética , Genes Dominantes , Alelos , Mapeamento Cromossômico , Distonia/classificação , Distonia/fisiopatologia , Distonia Muscular Deformante/classificação , Distonia Muscular Deformante/epidemiologia , Feminino , Variação Genética , Humanos , Masculino , Músculos/fisiopatologia , LinhagemRESUMO
The controversy regarding the mode of inheritance of idiopathic torsion dystonia in the Ashkenazi Jewish population has been resolved. At one time it was believed to be inherited as an autosomal recessive disorder. But recent studies, including a prospective, systematic, blinded analysis of the first- and second-degree relatives of 43 probands with age at onset less than 28 years found the disorder to be inherited in an autosomal dominant manner with a penetrance of approximately 0.30. Linkage analysis of Ashkenazi Jewish families with multiple affected members revealed that the gene for dystonia in this population is located in the q34 region of chromosome 9. This is the same region found to encode the dominant DYT1 gene for dystonia in a large non-Jewish family with a penetrance of about 0.70. It is likely that the disorder in these two ethnic populations may be caused by the same locus, and that the difference in penetrance may reflect different mutations operating in these two populations. We have found no evidence for genetic heterogeneity in the Ashkenazi Jewish families studied for linkage analysis, but there is at least one non-Jewish family with idiopathic torsion dystonia that is not linked to this region. Allelic association in 9q34 in the Ashkenazi Jewish population has narrowed the dystonia gene to a region of less than 2 cM.
Assuntos
Distonia Muscular Deformante/genética , Alelos , Distonia Muscular Deformante/classificação , Ligação Genética , Heterozigoto , Humanos , JudeusRESUMO
Some patients with dystonic movements and postures not known to be caused by environmental or degenerative disorders can be segregated from classical-appearing idiopathic torsion dystonia on the basis of distinctive clinical and pharmacologic features. Many of them should be considered within the family of dystonia, as clinical variants of idiopathic torsion dystonia, while others are better classified as being part of other families of dyskinesias. In the former group are paradoxical dystonia, myoclonic dystonia, diurnal dystonia, and dopa-responsive dystonia. The latter group consists of dystonic tics and the various entities comprising paroxysmal dystonia, namely kinesigenic, nonkinesigenic and hypnogenic dystonia.