Genetic classification and molecular mechanisms of primary dystonia*★

BACKGROUND： Primary dystonia is a heterogeneous disease, with a complex genetic basis. In previous studies, primary dystonia was classified according to age of onset, involved regions, and other clinical characteristics. With the development of molecular genetics, new virulence genes and sites have been discovered. Therefore, there is a gradual understanding of the various forms of dystonia, based on new viewpoints. There are 15 subtypes of dystonia, based on the molecular level, i.e., DYT1 to DYT15. OBJECTIVE： To analyze the genetic development of dystonia in detail, and to further investigate molecular mechanisms of dystonia. RETRIEVAL STRATEGY： A computer-based online search was conducted in PubMed for English language publications containing the keywords ＂dystonia and genetic＂ from January 1980 to March 2007. There were 105 articles in total. Inclusion criteria： ① the contents of the articles should closely address genetic classification and molecular mechanisms of primary dystonia; ② the articles published in recent years or in high-impact journals took preference. Exclusion criteria： duplicated articles. LITERATURE EVALUATION： The selected articles were on genetic classification and molecular genetics mechanism of primary dystonia. Of those, 27 were basic or clinical studies. DATA SYNTHESlS： ① Dystonia is a heterogeneous disease, with a complex genetic basis. According to the classification of the Human Genome Organization, there are 15 dystonia subtypes, based on genetics, i.e., DYT1-DYT15, including primary dystonia, dystonia plus syndrome, degeneration plus dystonia, and paroxysmal dyskinesia plus dystonia.② To date, the chromosomes of 13 subtypes have been localized; however, DYT2 and DYT4 remain unclear. Six subtypes have been located within virulence genes. Specifically, torsinA gene expression results in the DYTI genotype; autosomal dominant GTP cyclohydrolase 1 gene expression and recessive tyrosine hydroxylase expression result in the DYT5 genotype, respectively; the epsil     

颈肌张力障碍的发病机理和临床特点

颈肌张力障碍是成人局限性肌张力障碍中最常见的一种类型。本文就其流行病学、临床表现、发病机理、诊断分型的国外研究情况作一简要综述。     

Establishing motor disorder mouse models of Parkinson disease——Comparison of 6-hydroxydompamine and l-methyl-4-phenyl-l,2,3,6-tetrahdropyridine

BACKGROUND: At present, pathogenesis and mechanism of Parkinson disease (PD) are still unclear. Animal models of PD are essential tools in studies on etiology and therapy and should mimic the chronic pathological process, histological characteristics and motor behavior dysfunction. In recent years, transgenic mice have been widely utilized to study the mechanism of PD, and it has become imperative that a PD mouse model of motor behavioral dysfunction be established. OBJECTIVE: To compare the behavioral and histochemical characters of two neurotoxic mice model induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP), and a better method to mimic Parkinson disease will be found out. DESIGN: Parallel experiment. SETTING: Laboratory of Molecular Genetics, Department of Medical Genetics, Shanghai Jiao Tong University. MATERIALS: Sixty 129Sv/C57BL6J male wild mice, SPF grade, 8–12 weeks old, weighing 20–25 g, were provided by Experimental Animal Center, Shanghai Jiao Tong University. All the surgery operation was performed according to the rules of Shanghai Jiaotong University Animal Committee. METHODS: The experiment was carried out in the Laboratory of Molecular Genetics (National Key Laboratory), Department of Medical Genetics, Shanghai Jiao Ttong University from March to August 2006. ① Thirty-two male mice were randomly divided into control group and drug treatment group with 16 mice in each group. Surgery was carried out and 6-OHDA was administrated to substantia nigra pars compacta (SNpc) and nigra-striatum pathway according to the different parameters with intoxication apparatus. Saline was injected to the other 16 mice according to the same paradigm. 1 mg/kg apomorphine was injected intraperitoneally 2 weeks later after surgery to induce the imbalanced rotation behavior for 40 minutes. ② Twenty-eight mice were randomly divided into 4 groups with 7 in each group, including low-dose, moderate-dose, high-dose groups and negative control group. Then, mice in the drug treatment group were injected intraperitoneally with 5, 10 and 15 mg/kg MPTP for 9 successive days. In addition, mice in the control group were injected with the same volume of saline for 9 days. Pole test and stride length test were utilized to detect coordinative behavioral dysfunction. Mice were sacrificed 20 days after MPTP treatment, and histochemical staining of tyrosine hydroxynase (TH) was used to observe the loss of dopaminergic neuron in SNpc. MAIN OUTCOME MEASURES: ① Success ratio of each model establishment method; ② inducible asymmetric cycle behavior test 2 weeks after 6-OHDA injection; ③ behavioral dysfunction in pole test and stride length, morphological changes in brain tissue. RESULTS: Totally sixty mice were used in this experiment and 3 mice were excluded because of the hypersensitivity or the clumsy reaction in motor behavioral detection before MPTP treatment, therefore, data was analyzed with the rest 57 mice. ① Lethal ratio: Three out of 16 mice died in striatum injection group and 5 out of 16 mice died in nigro-striatal pathway group. No mouse died in MPTP treatment groups. ② Locomotor behavior: No dysfunction of locomotor was found in 6-OHDA treatment groups. However, several motor behavioral dysfunction were start to present at the 4th day of MPTP injection. ③ Asymmetric cycle behavior: No asymmetric cycle was induced successfully two weeks after 6-OHDA surgery. Mice show hypersensitive behavior 10 minutes after apomorphine injection, which lasted for about 20 minutes. ④ Pole test: From the 4th day of MPTP treatment, mice started to display coordinate dysfunction, such as climbing down along the pole in spiral, moving slowly with hesitation. Some mice could not grab the pole and slide down along the pole at 4th day post injection. Comparing with 0 dose control group, all the three drug treatment groups show significant different dysfunction from the 4th day to the 20th day post injection (P < 0.01). ⑤ stride length test: Mice's stride length decreased, when treated with MPTP, and the mice in the high dose group displayed obviously. ⑥ Dopaminergic neuron stained with TH in nigra pars compacta: The results indicated that administrated MPTP (from low dose to high dose) by intraperitoneal cause chronic lesions on the dopaminergic neuron in the SNpc. CONCLUSION: PD mice models induced with 6-OHDA show high mortality ratio and no asymmetric cycle was found after apomorphine injection. However, injection of MPTP intraperitoneally can simulate the chronic pathway of PD, typical histological changes are found and stable motor behavioral dysfunctions are displayed.     

多巴胺D2受体基因多态性与痉挛性斜颈易患性的相关性

原发型痉挛性斜颈（CD）是局灶型肌张力障碍中的一种最常见类型，其发病与遗传有关。由于三磷酸鸟苷环化水解酶Ⅰ基因的突变，DYT1基因编码的扭转蛋白A在黑质密部中表达，干扰多巴胺滤泡的运输，引起基底节多巴胺能神经递质的异常，从而导致了全身性肌张力障碍。     

颈部肌张力障碍肌肉疼痛的研究进展

颈部肌张力障碍是一种常见的局灶性肌张力障碍,主要临床表现为周期性头向一侧转动或前倾、后仰或固定于某一异常姿势.颈部肌张力障碍患者常有受累肌肉疼痛,疼痛症状严重影响患者生活质量和社会交往,而备受关注.然而目前关于颈部肌张力障碍肌肉疼痛的发病原因仍不明确,治疗方法也尚未形成一致意见.文中就近年来对颈部肌张力障碍肌肉疼痛的相...     

多巴反应性肌张力障碍10例临床特点分析

多巴反应性肌张力障碍（dopa-resposive dystonia,DRD）,又称Segawa病,是一种遗传缺陷造成纹状体多巴胺合成不足而导致的慢性运动障碍性疾病,好发于儿童或青少年,其主要症状是肌张力障碍或步态异常。早期诊断和及时治疗对改善患者预后非常重要,故现将于本科就诊的10例DRD患者的临床资料综合分析如下,以提高临床医生对此病的认识。     

帕金森病相关蛋白的作用研究进展

<正>帕金森病(Parkinsondisease,PD)是第二常见的神经变性疾病。其主要临床特征是静止性震颤、肌强直、运动减少和姿势平衡障碍等;主要病理改变是中脑黑质多巴胺能神经元进行性变性坏死,残存神经元中Lewy小体形成。5-10%帕金森病患者有家族史。虽然,大部分帕金森病病例为散发型,但阐明家族性帕金森病的分子机理对于整个帕金森病发病机制的研究有着重大的意义。本文就目前已经明确的帕金森病相关蛋白的作用机理作一综述。一、α-synucleinSCNA(PAPK1)是第一个被发现的与常染色体显性遗传帕金森病有关的基因,其编码蛋白α-synuclein。α-synuelein是一种高度保守的蛋白质,高度耐热,为小分子酸性蛋白质,含有140个氨基酸。α-synuclein的序列可以分为三个结构域高度保守的氨基端包含11个氨基酸不完全的6拷贝重复,中间部分是被称为非口-淀粉样蛋白(NAC)的疏水结构域,羧基端没有固定的结构原件。α-synuclein在中枢神经系统内(特别是突触前膜)丰富表达,定位于核周。它是一种可溶的,天然伸展的蛋     

快发病性肌张力障碍-帕金森综合征

快发病性肌张力障碍-帕金森综合征（RDP）是一种临床特征为应激后快速发病,以肌张力障碍和帕金森综合征为主要表现的肌张力障碍类疾病,由ATP1A3基因突变致Na＋,K＋-ATPase酶泵的α3亚单位酶活性或稳定性异常,引起小脑与基底节间功能协调异常所致;与相同基因发生突变引起的儿童交替性偏瘫等疾病可能有连续性表型疾病谱,值得不断深入探究.     

Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration： implications for the pathogenesis of Parkinson＇s disease

While the cause of dopaminergic neuronal cell death in Parkinson＇s disease（PD）is not yet understood,many endogenous molecules have been implicated in its pathogenesis.β-phenethylamine（β-PEA）,a component of various food items including chocolate and wine,is an endogenous molecule produced from phenylalanine in the brain.It has been reported recently that long-term administration ofβ-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins.The toxicity ofβ-PEA has been linked to the production of hydroxyl radical（.OH）and the generation of oxidative stress in dopaminergic areas of the brain,and this may be mediated by inhibition of mitochondrial complex-I.Another significant observation is that administration ofβ-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents.However,no reports are available on the extent of dopaminergic neuronal cell death after administration ofβ-PEA.Based on the literature,we set out to establishβ-PEA as an endogenous molecule that potentially contributes to the progressive development of PD.The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption ofβ-PEA-containing foods is proposed here.Thus,long-term over-consumption of food items containingβ-PEA could be a neurological risk factor having significant pathological consequences.     

肌张力障碍的治疗进展

肌张力障碍(dystonia)最早由Oppenheim于1911年提出,用来命名一种以躯体扭曲,肌肉痉挛,伴有身体屈曲的奇异步态以及逐渐出现的持续固定的姿态畸形为特征的儿童起病的全身性肌张力障碍。一个世纪以来,肌张力障碍的     

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

IntroductionIn dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations.MethodsConcentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites.ResultsA significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (r_s = −0.3, p < 0.01), depression (r_s = −0.3, p < 0.01) and fatigue (r_s = −0.2, p = 0.04).ConclusionThis study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.     

Striatal dopaminergic system in dopa-responsive dystonia: a multi-tracer PET study shows increased D2 receptors

Summary. We investigated the integrity of striatal dopaminergic system in seven patients with dopa-responsive dystonia (DRD). Dopamine transporter function ([¹¹C]CFT) and D1 ([¹¹C]NNC 756) and D2 receptors ([¹¹C]raclopride) were studied in same patients using positron emission tomography. Compared to age-adjusted control values the dopamine D2 receptor availability was increased in DRD. The mean age-adjusted [¹¹C]raclopride uptake was 116% of the control mean in the putamen (p=0.004) and 114% in the caudate nucleus (p=0.007). The mean [¹¹C]NNC 756 uptake was not different between DRD patients and controls, the age-adjusted uptake in DRD being 93% of mean control value in the putamen (p=0.20) and 95% in the caudate nucleus (p=0.40).The dopamine transporter binding was not altered. The [¹¹C]CFT uptake in DRD was 96% of the control value in the putamen (p=0.64), and 95% in the caudate nucleus (p=0.44).In conclusion, striatal dopamine D2 receptors availability is increased in DRD whereas dopamine D1 receptors and dopamine transporter ligand binding is unchanged. The pattern of changes in striatal dopaminergic system in DRD is different from that reported in juvenile Parkinsons disease. The increased D2 receptor availability may be due to reduced competition by endogenous dopamine or a compensatory response to dopamine deficiency, or both.     

Patient-based outcomes of cervical dystonia: a review of rating scales.

Decisions on treatment choice for patients are based on trials and outcome studies that are wholly dependent upon the scientific quality of the rating scales used. This study reviewed rating scales used in cervical dystonia outcome research to determine the extent that they satisfy recommended criteria for rigorous measurement.     

Structural white matter abnormalities in patients with idiopathic dystonia

We investigated whether structural white matter abnormalities, in the form of disruption of axonal coherence and integrity as measured with diffusion tensor imaging (DTI), constitute an underlying pathological mechanism of idiopathic dystonia (ID), independent of genotype status. We studied seven subjects with ID: all had cervical dystonia as their main symptom (one patient also had spasmodic dysphonia and two patients had concurrent generalized dystonia, both DYT1‐negative). We compared DTI MR images of patients with 10 controls, evaluating differences in mean diffusivity (MD) and fractional anisotropy (FA). ID was associated with increased FA values in the thalamus and adjacent white matter, and in the white matter underlying the middle frontal gyrus. ID was also associated with increase in MD in adjacent white matter to the pallidum and putamen bilaterally, left caudate, and in subcortical hemispheric regions, including the postcentral gyrus. Abnormal FA and MD in patients with ID indicate that abnormal axonal coherence and integrity contribute to the pathophysiology of dystonia. These findings suggest that ID is not only a functional disorder, but also associated with structural brain changes. Impaired connectivity and disrupted flow of information may contribute to the impairment of motor planning and regulation in dystonia. © 2006 Movement Disorder Society     

White matter abnormalities in gene‐positive myoclonus‐dystonia

Myoclonus‐dystonia is an autosomal dominantly inherited movement disorder clinically characterized by myoclonic jerks and dystonic movements of the upper body. Functional imaging and structural gray matter imaging studies in M‐D suggest defective sensorimotor integration and an association between putaminal volume and severity of dystonia, possibly because of neuronal plasticity. As we expect changes in the connections between the cortical and subcortical regions, we performed a combination of white matter voxel‐based morphometry (wVBM) and diffusion tensor imaging (DTI) to detect macro‐ and microstructural white matter changes, respectively, in DYT‐11 mutations carriers (M‐D). Sixteen clinically affected DYT‐11 mutation carriers and 18 control subjects were scanned with 3‐Tesla MRI to compare white matter volume, fractional anisotropy, and mean diffusivity between groups. In DYT11 mutation carriers, increased white matter volume and FA and decreased mean diffusivity werefound in the subthalamic area of the brain stem, including the red nucleus. Furthermore, decreased mean diffusivity was found in the subgyral cortical sensorimotor areas. The white matter changes found in the subthalamic area of the brain stem, connecting the cerebellum with the thalamus, are compatible with the hypothesis that abnormal function in M‐D involves a network that includes the cerebellum, brain stem, and basal ganglia. Whether these changes are causative or an effect of M‐D requires further study. © 2012 Movement Disorder Society     

Adult-onset primary lower limb dystonia.

The lower extremity is affected infrequently in adult-onset primary dystonia in contrast to childhood-onset dystonia, which typically begins in the foot. When dystonia affects the foot in an adult, it is usually on a secondary basis. We present findings on 17 patients (11 women, 6 men; average age of onset 48.4 years; average time to diagnosis 2.7 years) with adult-onset primary foot dystonia. Prior to diagnosis, most patients underwent extensive testing and treatment, including unnecessary surgeries. Only the left lower extremity was involved in 8 patients, only the right in 7, and both in 2. The most common patterns were plantar flexion of all toes and inversion of the foot, typically activated with standing or walking. Only 2 patients had dystonia elsewhere. There was a family history of possible dystonia in 2 patients. One of five tested for DYT1 was positive, in the absence of a family history. One of eight patients treated with levodopa experienced mild improvement. Six of eight treated with botulinum toxin improved. No patient has been observed to have a secondary cause of dystonia. The prognosis, with regard to progression or spread to other body parts, has been favorable. Although uncommon, foot dystonia on a primary basis, not due to DYT1, can begin in adulthood. In this series of patients, the diagnosis was often not recognized, leading to extensive and unnecessary testing and treatment and emphasizing the need for wider recognition.     

成年人的多巴反应性肌张力失常

目的 加强对多巴反应性肌张力失常的认识和重视。方法 回顾近2年我们诊治的3例成年人DRD患者之临床表现、辅助检查与治疗。结果 3例均为女性,无家族史。发病年龄14～29岁,平均20±7.94岁,平均误诊时间29.33±15.95年。表现为缓慢起病,四肢发僵,活动困难或伴有肢体震颤,足趾屈曲、内翻畸形;症状呈晨轻暮重。查体发现四肢肌张力强直性或齿轮样增高,双下肢腱反射活跃至亢进,1例病理征可疑阳性和脊柱前屈。辅助检查:血清学检查、CSF、头颅CT或MRI和神经电生理检查均正常。用小剂量复方左旋多巴有显著改善,平均剂量为98.21±49.17mg/d,使用最长者已达14年,无需增加剂量。结论 本病为少见的运动障碍疾病,在诊断中应与帕金森病鉴別。小剂量复方左旋多巴有显著、持久的疗效,早期应用安坦、金刚烷胺也有效。     

Treatment of cervical dystonia hand spasms and laryngeal dystonia with botulinum toxin

Summary One hundred and twenty-six patients with different forms of focal dystonia (89 with cervical dystonia, 12 with hand cramps and 25 with laryngeal dystonia) were treated with localised injections of botulinum toxin. Mean doses per muscle were 200 mouse units (m.u.) for treating cervical dystonia, 40–120 m.u. for forearm muscles in writers' cramp and 3.7 m. u. for the thyroarytenoid muscle in laryngeal dystonia. Responder rates have been above 80% in all patient groups and beneficial effects could be reproduced over follow-up periods of up to 4 years. The commonest side-effects were dysphagia after treatment of spasmodic torticollis, weakness of neighbouring muscles after injections for hand cramps and breathiness and hypophonia following laryngeal injections. All these were transient and generally well tolerated. It is concluded that botulinum toxin injections are a safe and effective treatment in all three types of focal dystonia.