Update on the Genetics of Dystonia

Mainly due to the advent of next-generation sequencing (NGS), the field of genetics of dystonia has rapidly grown in recent years, which led to the discovery of a number of novel dystonia genes and the development of a new classification and nomenclature for inherited dystonias. In addition, new findings from both in vivo and in vitro studies have been published on the role of previously known dystonia genes, extending our understanding of the pathophysiology of dystonia. We here review the current knowledge and recent findings in the known genes for isolated dystonia TOR1A, THAP1, and GNAL as well as for the combined dystonias due to mutations in GCH1, ATP1A3, and SGCE. We present confirmatory evidence for a role of dystonia genes that had not yet been unequivocally established including PRKRA, TUBB4A, ANO3, and TAF1. We finally discuss selected novel genes for dystonia such as KMT2B and VAC14 along with the challenges for gene identification in the NGS era and the translational importance of dystonia genetics in clinical practice.     

Genetics in Dystonia: An Update

Posterior cortical atrophy (PCA) is a group of neurodegenerative dementing disorders characterized by initial predominant visual complaints followed by progressive decline in cognitive functions. The visuospatial and visuoperceptual defects arise from the dysfunction of, respectively, the dorsal (occipito-parietal) and the ventral (occipito-temporal) streams. Clinical symptoms, results of neuropsychological examination, and findings of posterior cerebral atrophy and/or posterior hypoperfusion/hypometabolism contribute to the diagnosis. However, owing to the insidious onset of PCA and the non-specificity of initial symptoms, the diagnosis is often delayed. Specific etiologies include Alzheimer’s disease, dementia with Lewy bodies, subcortical gliosis, corticobasal degeneration, and prion-associated diseases. Alzheimer’s disease accounts for at least 80 % of PCA cases. Recent research has concentrated on better defining the clinical presentation of PCA, improving neuroimaging analysis, testing new neuroimaging techniques, and developing biological measurements. Selected recent papers on PCA are reviewed in this article.     

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

Isolated inherited dystonia—formerly referred to as primary dystonia—is characterized by abnormal motor functioning of a grossly normal appearing brain. The disease manifests as abnormal involuntary twisting movements. The absence of overt neuropathological lesions, while intriguing, has made it particularly difficult to unravel the pathogenesis of isolated inherited dystonia. The explosion of genetic techology enabling the identification of the causative gene mutations is transforming our understanding of dystonia pathogenesis, as the molecular, cellular and circuit level consequences of these mutations are identified in experimental systems. Here, I review the clinical genetics and cell biology of three forms of inherited dystonia for which the causative mutation is known: DYT1 (TOR1A), DYT6 (THAP1), DYT25 (GNAL).     

扭转痉挛患者基底节的电生理研究

目的 观察扭转痉挛患者基底节神经元的电活动特点。方法 在对6例扭转痉挛患者行微电极导向脑内核团毁损术治疗的同时,利用微电极记录技术分别对4例患者的内苍白球、2例患者的丘脑底核神经元电活动进行了记录和分析。结果 内苍白球神经元主要表现为高度不规律的持续低频群发放电,间有暂歇,其平均自发放电频率为(26.4±13.9)Hz,电活性较低。丘脑底核神经元主要表现为不规律的发放,其平均自发放电频率为(49.1±9.2)Hz,电活性较高。结论 扭转痉挛患者基底节存在功能异常。     

Parieto-motor Cortical Dysfunction in Primary Cervical Dystonia

BackgroundDystonia is considered as a motor network disorder involving the dysfunction of the posterior parietal cortex, a region involved in preparing and executing reaching movements.Objective/hypothesisWe used transcranial magnetic stimulation to test the hypothesis that cervical dystonic patients may have a disrupted parieto-motor connectivity.MethodsWe enrolled 14 patients with primary cervical dystonia and 14 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area. Changes in the amplitudes of motor evoked potential were analyzed as an index of parieto-motor effective connectivity. Patients and healthy subjects were also evaluated with a reaching task. Reaction and movement times were measured.ResultsIn healthy subjects, but not in dystonic patients, there was a facilitation of motor evoked potential amplitudes when the conditioning parietal stimulus preceded the test stimulus applied over the primary motor area by 4 ms. Reaction and movement times were significantly slower in patients than in controls. In dystonic patients, the relative strength of parieto-motor connectivity correlated with movement times.ConclusionsParieto-motor cortical connectivity is impaired in cervical dystonic patients. This neurophysiological trait is associated with slower reaching movements.     

肌张力障碍

肌张力障碍（dystonia）为一组临床综合征，系指主动肌与拮抗肌间歇性不协调收缩或过度的持续性收缩所引起的肢体重复性不自主运动和姿势异常，可伴有疼痛。其分类可按病因、发病年龄、受累部位等进行划分；传统的治疗方法主要包括药物治疗、外科手术及支持治疗，20世纪80年代后期，肉毒杆菌毒素开始用于多种肌张力障碍的治疗。最近的研究显示，外科手术尤其是脑深部电刺激术对全身性和局限性肌张力障碍的治疗有效。[第一段]     

Dystonia

Dystonia, a hyperkinetic movement disorder, is characterized by involuntary muscle spasms leading to abnormal postures. Dystonic syndromes are classified by etiology (primary vs. secondary), age of onset (early vs. late onset) or spread of symptoms (focal, segmental, generalized). Clinically, young-onset dystonia is rare, often inherited and tends to spread to become generalized. In contrast, adult-onset dystonia is frequent, typically sporadic and remains focal. In recent years, 15 genes associated with dystonia have been identified and classified as DYT loci. Of these, DYT1 is the most frequent, causing early-onset generalized dystonia. Pathophysiology remains ill understood but basal ganglia dysfunction is thought to play an important role. Treatment remains symptom-oriented. A trial of levodopa is recommended in young-onset cases. In focal forms, botulinum toxin injections are helpful. Anticholinergics may be beneficial. In severe cases deep brain stimulation may be considered.     

Dystonia update

PURPOSE OF REVIEW: Dystonia is a movement disorder with a complex and not fully understood pathophysiology. Its better understanding would enable more focused treatment for the disorder. In this review, we provide an overview of recent studies of the pathophysiology of primary and secondary dystonia, with an emphasis on functional brain imaging. Potential mechanisms underlying the beneficial effects of deep brain stimulation for dystonia are also summarized. RECENT FINDINGS: The recognition of dysfunction at different levels of the nervous system has extended the classical notions of localized striatal abnormalities in primary dystonia. Recent biochemical studies have revealed evidence of abnormal torsion activity in DYT1 dystonia. Abnormal patterns of brain metabolism have also been identified using functional brain imaging in different dystonia genotypes. These findings, in conjunction with new electrophysiological techniques, can be utilized to help define a common mechanism for the neural dysfunction in dystonia. SUMMARY: New insights into the pathophysiology of dystonia have been provided by recent studies using electrophysiology, biochemistry and human genetics, as well as functional brain imaging studies. These advances together may create the basis for new therapies for this disorder.     

Tardive Dystonia

In a population of 200 consecutive inpatients with a history of at least 3 months' total cumulative neuroleptic exposure, the prevalence of tardive dystonia (TDt) was 4%, higher than previously reported. The prevalence of tardive dyskinesia (TDk) was 22%. Patients with TDt did not differ in demographic or clinical variables from nondyskinetic patients. In comparison with patients with TDk, patients with TDt were significantly younger, had a more severe movement disorder, and had received neuroleptics for the first time fewer years before. Patients with TDk were significantly older than patients without tardive disorders, both when they were examined and when they had started their first neuroleptic treatment. Furthermore, they had started their first neuroleptic treatment more years before. These results support the distinction between TDt and TDk, and suggest that the previously reported prevalence of TDt might have been underestimated.     

特殊工作性肌张力障碍

特殊工作性肌张力障碍是一种特殊形式的局灶性肌张力障碍。常见症状有书写痉挛和音乐家手部痉挛等，症状的出现多与职业行为相关。病因尚不明，目前的研究认为过度的活动、基底节功能障碍、大脑皮质运动和感觉功能异常及一定的遗传背景可能与之有关。在治疗方面，除了常规的口服药物治疗外，肉毒毒素注射、支具固定制动和行为治疗等特殊方法有较好的疗效。     

Dystonia update

Dystonia is a syndrome of sustained muscle spasms of presumed central nervous system origin. Recent advances in molecular biology have permitted clearer understanding of the genetics of various forms of dystonia and suggest pathophysiological deficits at the origin of the clinical signs. Treatment has involved centrally-acting drugs, specifically the anticholinergic medications, as well as peripherally acting agents that block neuromuscular transmission (botulinum toxin). Some forms of dystonia are particularly responsive to levodopa. A systematic approach to the diagnostic and treatment evaluation of dystonic patients permits optimal care for long-term management.     

Treatment of Dystonia

Selecting the appropriate treatment for dystonia begins with proper classification of disease based on age, distribution, and underlying etiology. The therapies available for dystonia include oral medications, botulinum toxin, and surgical procedures. Oral medications are generally reserved for generalized and segmental dystonia. Botulinum toxin revolutionized the treatment of focal dystonia when it was introduced for therapeutic purposes in the 1980s. Surgical procedures are available for medication-refractory dystonia, markedly affecting an individual’s quality of life.