家族性发作性运动诱发性运动障碍六个家系的临床及遗传特点分析

目的探讨发作性运动诱发性运动障碍（paroxysmal kinesigenic dyskinesia，PKD）的临床特征及遗传特点。方法对6个中国汉族PKD家系共122名成员进行随访，包括患者26例，总结分析其临床表现、遗传特点、辅助检查及预后。结果本组6个家系共有患者26例，其中男性18例，女性8例（男：女=2．25：1）。患者发病年龄为4～30岁，均以突然运动诱发，表现为肢体的不能控制的肌张力障碍、舞蹈、投掷样动作等，每次发作约持续几秒到十几秒，持续时间最长不超过1min，平均每天发作数次，不伴意识障碍。神经系统检查、脑电图、头颅影像学检查等均无阳性发现。多数患者可自然缓解，抗癫痫药物治疗有效。6个家系中4个家系有连续2代以上发病，符合常染色体显性遗传；2个家系只有一代患者，且均为同胞兄弟／姐妹，符合常染色体隐性遗传。通过家系内比较，发现4个显性遗传家系均有子代较父代发病年龄提前、发作频率增加、病程延长等现象，提示存在遗传早现（anticipation）。结论PKD是一种神经系统的常染色体遗传病，既有显性遗传又有隐性遗传，具有遗传和临床异质性（heterogeneity）。中国汉族人群中显性遗传的PKD家系存在遗传早现现象。     

发作性运动诱发性运动障碍八个家系临床特点分析

目的分析及探讨家族性发作性运动诱发性运动障碍（PKD）的临床特征、诊断和治疗特点。方法观察8个PKD家系的临床表现，进行家系调查分析，对患者进行脑电图或视频脑电图、头颅磁共振成像（MRI）或CT检查。结果8个家系共有患者28例，男性20例，女性8例，发病年龄8～18岁，平均10．8岁。全部患者均表现为突然运动诱发的一侧或双侧异常运动，发作时间短于1min，发作时意识清楚；发作间期均无神经系统阳性体征。同一家系中患者症状轻重不一，随年龄增大发作逐渐减少，以至消失。脑电图、视频脑电图及头颅影像学均未发现明显异常。患者使用抗癫痫药物治疗有效。结论PKD是发作性异常运动中常见的一种，突然运动诱发是其主要特点，家族性患者不少见，主要遗传方式是常染色体显性遗传，有外显不全现象，不排除有其他的遗传方式。临床发作形式与癫痫不同，但抗癫痫药物治疗有效。     

发作性运动诱发性运动障碍一家系临床与遗传学特点

目的探讨家族性发作性运动诱发性运动障碍(paroxysmal kinesigenic dyskinesia,PKD)临床及遗传学特点。方法对1个PKD家系共14名成员进行PRRT2基因检测及调查随访,其中患病2例(1例住院治疗,另1例未治疗),总结分析其临床表现、遗传特点、药物治疗效果及预后。结果该家系2例患者均为男性,患病率14.3%,其中1例不治自愈,1例用卡马西平疗效显著,用拉莫三嗪也有效。该家系为单纯性PKD家系,PRRT2基因检测结果显示该家系中3例存在突变c.797GA(p.266RQ),其中1例无临床症状,符合常染色体显性遗传,伴不全外显,存在遗传早现;该家系合并存在多囊肾家族史。结论单纯家族性PKD抗癫痫药物疗效与突变类型及临床特征有关;治疗方案选择应以临床特点及突变类型为依据。     

家族性特发性震颤6家系临床及遗传特点分析

目的 分析家族性特发性震颤(familial essential tremor,FET)的临床特点,探讨该病的分子遗传学进展.方法 回顾性分析6个家族性特发性震颤家系的临床及遗传学特征.结果 6个家系共32例患者,男22例,女10例,发病年龄25～71岁,其中家系A中有2例患者合并甲状腺功能亢进症,家系B与C中各有1例伴听力下降.除F外的5个家系有连续2代以上发病,符合常染色体显性遗传,且有遗传早现现象.家系F只有一代患者,但3名同胞均患病.结论 FET呈现出常染色体显性遗传的特点,存在临床和遗传异质性.迄今已发现FET存在多个遗传位点,但尚未找到确切的致病基因.     

家族性发作性睡病(附4例报告及家系调查)

本文报告4例发作性睡病,均呈家族性发生,并进行了家系调查。对四个家族的16例患者的症状分析发现,本组除主症睡眠发作外,伴睡眠瘫痪者居多,占9例(56.2％),而猝倒发作的发生率却很低,仅占2例(12.5％)。家系调查结果提示,本病与遗传有密切关系,其遗传方式可能是常染色体显性遗传。     

发作性运动诱发性舞蹈指痉症

目的：探讨发作性运动诱发性舞蹈指痉症（PKC）的临床特点，进一步提高对该病的诊治水平。方法：对5例PKC患者的临床表现及实验室资料进行分析。结果：5例患者来自2个家系，发病年龄13-16岁；临床表现均在运动开始时出现不自主手足及面部异常运动，持续数秒后自行缓解，紧张、恐惧时易发，克制可避免发作。5例检查12例次脑电图，均未见癫痫样放电；3例头颅MRI及T3、T4，血沉、血钙均在正常范围。3例脬用妥泰（100mg/d），完全控制发作，2例间断服苯英钠，亦有效。结论：PKC可能为常染色体显性遗传。临床表现以开始运动时出现发作性锥体外系症状为特征。抗癫痫药治疗效果良好。     

中国家族性帕金森病的遗传和临床特点(附28个家族分析)

目的研究家族性帕金森病(PD)的遗传和临床特点。方法收集近50多年以来国内报道的所有PD家系的资料，分析28个PD家族的起病年龄、遗传方式、临床表现等特点。结果家族性PD的发病年龄早于人群平均发病年龄，主要为常染色体显性遗传，同一家族的患者症状和体征大多相似，以震颤为主(60．7％)，部分家族有早发的遗传特征。结论临床工作中应注重对PD患者Ⅰ、Ⅱ级亲属的询问和体检，以有利于家族性PD的早期发现和治疗。     

发作性动作诱发性运动障碍临床表现及遗传学研究进展

发作性动作诱发性运动障碍是一组由突然动作所诱发的非随意运动障碍性疾病,具有高度临床及遗传异质性。家族性发作性动作诱发性运动障碍大多呈常染色体显性遗传,PRRT2基因被证实为其致病基因。迄今为止,共明确56种PRRT2基因突变类型,其中大部分为无义突变,但无明确的基因型和表型关联性。有关PRRT2蛋白功能尚未阐明,但其与突触相关蛋白25的相互作用可能为进一步研究发作性动作诱发性运动障碍的发病机制带来提示。     

我国学者关于家族性发作性运动诱发性运动障碍基因克隆的研究结果在Nature Genetics在线发表

发作性运动诱发性运动障碍( paroxysmal kinesigenic dyskinesia,PKD)是一种反复发作的、运动诱发的、持续时间短暂的运动障碍,卡马西平治疗有显著疗效,临床上易被误诊为癫痫.自1967年Kertesz首次报道后,陆续有关于散发性和家族性病例的报道,推测其发病率约为1/150000,家族性病例大多呈常染色体显性遗传.从上世纪90年代起,先后有学者通过连锁分析将PKD的致病基因定位于16号染色体的2个区域(16p11.2-q12.1,16q13-q22.1),但一直未克隆到其致病基因.     

单纯型家族性发作性运动诱发性运动障碍二家系基因连锁分析

目的 对2个中国汉族单纯型发作性运动诱发性运动障碍(PKD)大家系进行排除定位,为PKD发病机制的探讨及疾病基因的克隆奠定基础.方法 抽取2个家系27名成员外周血,选取16号染色体上覆盖目前已知PKD位点的微卫星标记,进行参数及非参数连锁分析,并进行单体型分析.结果 通过对2个显性遗传的PKD大家系的参数及非参数连锁分析发现,家系A的最大LOD值以及NPL值均为负值,P＞0.05,排除与已知的PKD位点连锁;家系B的最大LOD值＜1,最大NPL值0.77,P＞0.05,不支持致病基因与已知PKD位点连锁.进一步对2个家系进行单体型分析,排除其致病基因位点与已知位点连锁,提示存在新的PKD疾病基因位点.结论 PKD具有遗传异质性,单纯型PKD家系存在新的疾病基因位点.     

Clinical manifestations of 20 Taiwanese patients with paroxysmal kinesigenic dyskinesia

Introduction - We compared the clinical manifestations and response to medications between familial and sporadic patients with paroxysmal kinesigenic dyskinesia (PKD), and also between patients with autosomal dominant (AD) and autosomal recessive (AR) inheritance. Material and methods - This retrospective cohort study included 9 familial and 11 sporadic Taiwanese patients with PKD diagnosed during a 10-year period at one of two hospitals. The mean duration of follow-up was 2.7 years. Each patient was interviewed and their medical records, as well as videotape recordings of PKD attacks in 6 patients, were used for analysis. Patients were treated with either carbamazepine or phenytoin, and the efficacy of sodium valproate was tested in 5 patients. Results - No single distinguishing feature in terms of clinical manifestations or therapeutic response was found to differentiate among familial, and sporadic cases, or between AD and AR inheritance. Carbamazepine and phenytoin were superior to sodium valproate in treating both familial and sporadic PKD patients, and both drugs resulted in almost complete remission of attacks. Conclusion - Our findings indicate that the sporadic and familiar forms of PKD, as well as the AR and AD inherited types, are similar in terms of clinical manifestations and response to treatment. The functional status and prognosis of our Taiwanese patients suggest that PKD is a relatively benign entity.     

Anticipation and phenotype in familial intracranial aneurysms

BACKGROUND: In familial intracranial aneurysms there is evidence for genetic heterogeneity, probably from mutations at separate loci. OBJECTIVES: To compare demographic and clinical features in patients of families with familial intracranial aneurysm and different patterns of inheritance; and to compare the ages of patients with subarachnoid haemorrhage (SAH) in affected parent-child pairs to determine whether there is anticipation. METHODS: Pedigrees for 53 families with familial intracranial aneurysms were constructed, divided into patterns of inheritance suggestive or not suggestive of autosomal dominant transmission. Demographic and clinical features were compared. The age at time of SAH in affected parent-child pairs was compared using the Wilcoxon test. RESULTS: No differences in demographic or clinical features were found between families compatible with an autosomal dominant pattern of inheritance and those with a non-dominant pattern. In families with affected members in two successive generations the age at time of SAH in parents was 55.2 years and in children 35.4 years (mean difference, 19.8 years, p<0.001). CONCLUSIONS: Phenotypes are similar in families with and without a probable autosomal dominant pattern of inheritance. Thus in future genetic studies on familial intracranial aneurysms, stratification according to phenotype is not likely to be useful. Anticipation probably occurs, as affected parents are significantly older at the time of SAH than their affected children.     

The inheritance of Alzheimer's disease: a new interpretation

Ninety-one families of Alzheimer patients were studied to determine the proportion of familial cases, to obtain pedigrees for the analysis of the mode of inheritance, and to look for clinical differences between the familial and the nonfamilial cases. The diagnosis was confirmed by autopsy in 26 cases. Thirty-nine cases (43%) were familial, which is defined as more than one case in the family. Our interpretation of the pedigree data is that Alzheimer's disease is etiologically heterogeneous: it may be genetic or sporadic. In the familial type we think that the disease is inherited as an autosomal dominant, with a wide range of age of onset within a family. In one-third of these families the gene is not expressed until over age 70. No clinical differences were found between the familial and the sporadic groups.     

Paroxysmal kinesigenic dyskinesia: a channelopathy? Study of 19 cases

INTRODUCTION: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by brief episodes of dystonia and choreoathetosis triggered by sudden voluntary movements. Disease onset is seen in the first or second decade. The attacks typically last less than one minute. Three autosomal dominant PKD loci are identified: EKD1, EKD2 and EKD3. EKD1 has an overlap with the locus of the "Infantile Convulsion and Choreoathetosis (ICCA) syndrome". The favorable natural history, the episodic nature of the symptoms and their sensitivity to anticonvulsant therapy suggest channelopathy as a mechanism of PKD. PATIENTS AND METHODS: We reviewed the clinical features, the family history, the treatment response, the evolution and the technical investigations in 19 affected individuals. RESULTS: All cases were idiopathic. Ten patients had a positive familial history. Three patients suffered from ICCA syndrome. Some atypical features were seen, such as the association of kinesigenic and nonkinesigenic attacks and the presence of migraine, ataxia, seizures and myoclonus. Acetazolamide responsiveness was seen in two patients. CONCLUSION: The coexistence of PKD and nonkinesigenic dyskinesia in several patients confirms the earlier described presence of intermediary forms, nonrepresented in the current classification of paroxysmal dyskinesias. Our study results suggest channel dysfunction and basal ganglia involvement in the pathophysiology of PKD.     

发作性运动诱发性运动障碍临床表型分析

研究背景发作性运动诱发性运动障碍是一组由突然动作诱发的非随意性运动障碍性疾病,表现为反复发作的短暂性肌张力障碍或舞蹈样动作,具有高度临床和遗传异质性。本研究旨在总结中国发作性运动诱发性运动障碍临床表型特点。方法采集195例原发性发作性运动诱发性运动障碍患者临床资料,采用自行设计的发作性运动诱发性运动障碍登记表记录并整理,分析和总结发作性运动诱发性运动障碍临床表型特点,并比较家族性与散发性患者临床表型差异。结果 195例发作性运动诱发性运动障碍患者男女比例为4.42∶1,平均发病年龄为(12.32±3.49)岁,单纯型162例(83.08%)、复杂型33例(16.92%),16例(8.21%)合并特发性震颤,144例(73.85%)发作前有先兆,发作形式包括肌张力障碍(134例,68.72%)、舞蹈样动作(8例,4.10%)和二者混合形式(53例,27.18%),134例(68.72%)发作时面部受累,115例(58.97%)发作频率10次/d、54例(27.69%)10~20次/d、26例(13.33%)20~30次/d,117例(60%)发作持续时间10 s、58例(29.74%)10~30 s、20例(10.26%)30~60 s,散发性131例(67.18%)、家族性64例(32.82%),78例(40%)未服用药物,117例(60%)服用抗癫药物患者中106例症状完全控制、8例偶有发作、3例未见明显缓解。其中,家族性组发病年龄低于(t=2.376,P=0.019)、发作持续时间短于(χ~2=7.731,P=0.021)散发性组。结论通过大样本临床数据分析和总结中国发作性运动诱发性运动障碍临床表型特点,以期为临床诊断与治疗提供帮助。     

Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain

BACKGROUND: The relative contribution of mutations in the presenilin (PSEN) and amyloid precursor protein genes to autosomal dominant and other early-onset Alzheimer disease (AD) cases is not well established. OBJECTIVES: To clarify the respective contribution of the amyloid precursor protein and PSEN mutations to autosomal dominant AD and to determine its contribution to sporadic and familial nonautosomal dominant early-onset AD and familial late-onset AD in a referral-based Spanish population. SUBJECTS AND METHODS: Ninety-four patients with AD (60 with early-onset AD and 34 with late-onset AD) from 82 independent families were studied. According to the family history, patients were classified into the following groups: autosomal dominant, familial nonautosomal dominant, and sporadic. Mutational analysis of the coding regions of the amyloid precursor protein, presenilin 1, and presenilin 2 was performed in all patients. Apolipoprotein E was also genotyped. RESULTS: Of the 60 early-onset cases, 44 from 36 families had a positive family history (11 with autosomal dominant AD and 25 with familial nonautosomal dominant AD) and 16 were sporadic. The frequency of mutations was 54.6% (6/11) among the autosomal dominant group, 6.2% (1/16) among the sporadic group, and 4% (1/25) among the familial nonautosomal dominant AD group. Most PSEN mutations (92%) would have been detected using a cutoff age of 58 years. The apolipoprotein E epsilon4 allele frequency was increased among early-onset AD without PSEN mutations. CONCLUSIONS: More than half of the families with autosomal dominant early-onset AD can be explained by coding mutations in the PSEN genes. In the familial and sporadic early-onset groups mutations are rare. When family history is unavailable, an age of 58 years may be used as a cutoff point for genetic analysis. The increased apolipoprotein E epsilon4 allele in patients without PSEN mutations confirms that it is an important risk factor in the cause of non-PSEN early-onset AD.     

Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment

Two familial X-linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X-linked transmission. On the other hand, the pedigrees of 2 families ruled out X-linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X-linked syndrome of cortical maldevelopment.     

Hereditary thrombocytopenia due to reduced platelet production--report on two families and mutational screening of the thrombopoietin receptor gene (c-mpl)

Hereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.     

Familial pure paroxysmal kinesigenic dyskinesia in Han population from the Chinese mainland: A new subtype?

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurologic inherited disease with heterogeneity. Autosomal dominant (AD) is the common inherited mode. There have been two loci mapped to 16 chromosome for PKD. However, no gene responsible for it has been identified so far. We collected 6 pedigrees from Chinese mainland. There were 122 members in all, including 26 affected. According to New diagnostic criteria of Bruno, they were diagnosed as pure PKD. From the clinic data, we found that the onset age was earlier and the severity was increasing in the subsequent generations in 4 pedigrees of them, which suggested genetic anticipation. Linkage analysis was applied in 2 of these pedigrees. The maximum LOD score and NPL score were negative. The followed haplotypes analysis excluded the PKD locus in both families from chromosome 16, providing evidence for a novel locus.