遗传性共济失调临床和基因诊断进展

遗传性共济失调是一组以进行性平衡失调和肢体协调运动障碍为特征的疾病 ,由于基因异质性和表型变异错纵复杂 ,仅根据表型作出准确诊断较为困难。本文综述遗传性共济失调的临床表现和基因学研究进展 ,为正确诊断提供思路。诊断遗传性共济失调的一般顺序 :首先确认患者主要特征是共济失调并收集家族史资料 ,其次排除非遗传性病因 ,并检测有无特定的生化异常 ,最后做基因学检测。一、确认共济失调综合征并确定遗传特点典型病例表现进行性步行困难 ,伴笨拙、语言障碍或视觉障碍。眼震、吟诗样语言、辨距不良、震颤和步态共济失调等是主要的小脑…     

免疫相关运动障碍临床研究进展

神经系统自身免疫性疾病相关运动障碍在临床诊断中逐渐被认识,主要包括副肿瘤综合征、自身免疫性脑炎及免疫调节治疗相关运动障碍等。运动障碍可以是神经系统自身免疫性疾病的重要甚至首发表现,主要包括舞蹈病、肌张力障碍、帕金森综合征、震颤、刻板动作、肌阵挛、小脑共济失调等。本文拟对常见自身免疫性相关运动障碍的临床特点进行综述。     

遗传性脊髓小脑共济失调一家系13例报告

遗传性脊髓小脑共济失调(hereditary spinocerebellar ataxia)是一类单基因遗传的神经系统变性病,其中以常染色体显性遗传的脊髓小脑性共济失调(spinocerebellar ataxia,SCA)最为常见.国外现已经报道30余种亚型[1].本病的主要临床表现有小脑性共济失调、辨距不良、构音障碍、眼球震颤、眼肌麻痹、锥体束征、锥体外系征等,还可伴有神经系统以外的表现[2].国内外常见家系报道,本文报道以行走不稳及构音障碍为主要表现,且发病人数较多的一家系.     

多系统萎缩与脊髓小脑共济失调的鉴别诊断

<正>小脑性共济失调分为两大类:散发性和遗传性。多系统萎缩(multiple system atrophy,MSA)是一组成年期起病、散发性的神经系统变性疾病,主要分为两种临床亚型,包括以帕金森综合征为突出表现的临床亚型称为MSA-P型,以小脑     

以不自主抖动为首发表现的脊髓小脑性共济失调13型1病例报告

正常染色体显性遗传性小脑性共济失调(ADCA)也称为脊髓小脑性共济失调(Spinocerebellar ataxia type,SCA),是一种起病隐匿,缓慢加重的神经系统变性病。其临床表现非常广泛,包括小脑性共济失调、眼动障碍、锥体外系运动障碍、视神经萎缩、视网膜病变、认知障碍、周围神经病及癫痫等[1]。由于各亚型间存在着巨大的重叠,临床上对于特定亚型的诊断非常困难。随着基因检测技术的发展与应用,目前已鉴定出40余种亚型。     

表现为"纯小脑性"共济失调的SCA3/MJD一家系报告

遗传性脊髓小脑型共济失调(spinocerebellar ataxias, SCA)是一类包括多种亚型共济失调在内的进行性神经系统变性疾病,多为常染色体显性遗传.SCA具有明显的遗传和临床异质性.我们对1个临床诊断为SCA的家系进行了部分基因的CAG三核苷酸重复突变检测分析,报道如下.     

遗传性共济失调症(附五组家族报告)

报告遗传性共济失调五组家族共56例患者,其中E组为脊髓型(Friedrech共济失调),A～D组属小脑型,因有包括眼震的眼球运动障碍,更似遗传性痉挛性共济失调。A组家族同时有精神异常、近视、提示此三种表现可能是紧密相连的致病基因所致。认为以起病年龄及遗传形式作为遗传性共济失调症的临床分类基础较为简单。     

成人发病的散发性共济失调症临床诊疗

成人发病的散发性共济失调症是由多种原因所致,临床表现以共济失调为主要的多种疾病。致病原因包括中毒、免疫介导性、维生素缺乏、感染性疾病、变性病以及遗传性疾患等。散发性共济失调临床谱具有明显异质性,临床正确诊断极具挑战性。但相比于遗传性共济失调症,此类疾患多数治疗效果较好,及时、正确诊断尤为重要。现代生化、免疫以及影像学技术有助于此类疾患的认识和诊治。文中综述并讨论可致成人发病的散发性共济失调的不同疾病分类,并着重其临床和神经影像学表现及诊断标准。     

遗传性运动障碍临床试验研究的思考

运动障碍是一组以神经系统变性病为主的疾病群，临床表现有锥体外系受损的不随意运动，肌张力障碍，震颤，姿势异常以及锥体系、脊髓或周围神经受损的随意运动障碍。例如帕金森病、进行性核上麻痹、亨廷顿病、共济失调、肌张力障碍、多系统萎缩、肌萎缩侧索硬化、抽动一秽语综合征等；具有隐袭     

伴头颈部肌张力障碍的遗传性共济失调的临床特征

目的探讨伴头颈部肌张力障碍的遗传性共济失调的临床特征.方法对200余个遗传性共济失调家系进行回顾性分析.结果14个遗传性共济失调家系伴有痉挛性斜颈或头颈部不自主运动,所有家系呈常染色体显性遗传方式,先证者均表现为共济失调、痉挛性斜颈或头部震颤、构音障碍;2例头颈部震颤呈发作性,2例合并四肢震颤,1例合并躯干抖动,1例全身不自主抖动;患者智力大多正常,无感觉障碍;部分患者头部MRI检查示小脑萎缩而脑干和大脑受累不明显.结论伴头颈部肌张力障碍的遗传性共济失调十分罕见,呈常染色体显性遗传,小脑性共济失调和头颈部肌张力障碍是其重要特征.     

Ataxias. Diagnostic procedure and treatment

Ataxia disorders (or ataxias) include both hereditary and nonhereditary diseases of the cerebellum and spinal cord, all of which are clinically characterized by progressive ataxia. A distinction is made between ataxia disorders and focal diseases of the cerebellum (tumor, abscess, infarction, hemorrhage, demyelinating disease). Ataxias are classified according to the molecular causes, being divided into hereditary ataxias, sporadic degenerative ataxias, and acquired ataxias. The diagnostic tests to be applied should be selected to suit the individual clinical situation in each case. When a patient experiences disease onset before the age of 25 years and the disease affects only one generation autosomal recessive ataxias must be considered. If one of the patient's parents had a similar disease spinocerebellar ataxia (SCA) with a dominant autosomal mode of inheritance is probable. Patients with sporadic disease starting in adulthood may have an acquired ataxia, such as alcoholic cerebellar degeneration (ACD) or paraneoplastic cerebellar degeneration (PCD), or a sporadic degenerative ataxia, such as multiple system atrophy (MSA) or sporadic adult-onset ataxia (SAOA). Therapies based on the underlying molecular pathogenesis are available for a number of ataxia disorders.     

Familial cognitive impairment with ataxia with oculomotor apraxia

Ataxia with oculomotor apraxia is an autosomal recessive inherited disease characterized by childhood onset of progressive cerebellar ataxia, oculomotor apraxia, and progressive motor peripheral neuropathy. The mean age at onset is approximately 4.7 years, with oculomotor apraxia appearing a few years later. Diagnosis is based on molecular genetic analysis for mutations of the aprataxin (APTX) gene (chromosome 9p13.1; ataxia with oculomotor apraxia 1). Ataxia with oculomotor apraxia 2 is caused by an unknown gene mutation at locus 9q34. We describe two siblings, born to consanguineous parents, who had clinical features of cerebellar ataxia, tremor, dysarthria, oculomotor apraxia, and motor peripheral neuropathy. Brain magnetic resonance imaging showed cerebellar atrophy and mild brainstem atrophy. Electromyography showed signs of axonal neuropathy. The molecular genetic analysis demonstrated the APTX mutation W279X at locus 9p13.3 (ataxia with oculomotor apraxia 1 disease), and psychologic studies showed mild cognitive impairment. We suggest that mentation can be compromised in ataxia with oculomotor apraxia 1.     

Clinical features and molecular genetics of autosomal recessive spinocerebellar degenerations]

The number of patients with spinocerebellar degeneration (SCD) has recently exceeds 20,000 in Japan. Among them, sporadic form is the most common form (67.2%). Among the hereditary forms of SCD, autosomal dominant (AD) form comprises 27.0%, while autosomal recessive (AR) form is rare (1.8%). Because of the rare occurrence of AR-SCD, the molecular genetic studies have been difficult to conduct. Recent progresses in molecular genetics, however, have enabled identification of causative genes for the majority of AR-SCD. Although Friedreich's ataxia is the most representative form of AR-SCD, patients with molecular diagnosis of Friedreich's ataxia have not been described in the Japanese population. Among the various forms of AR-SCD, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) seems to be the most common form in the Japanese population. Aprataxin, the causative gene for EAOH, has been suggested to play a role in the single strand DNA break repair. Interestingly, abnormalities in DNA break repair processes have been implicated in several forms of AR-SCD including AOA2, SCAN1 and ataxia telangiectasia. In this group of AR-SCD, cerebellar atrophy is more marked compared to that observed in Friedreich's ataxia. Taken together, abnormalities in DNA break repair processes may play an essential role in cerebellar degeneration in this group of AR-SCD.     

Milestones in ataxia

The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias, resulting in improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias, ataxia telangiectasia, and Friedreich ataxia. To date, the causative mutations of more than 30 spinocerebellar ataxias and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes, so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathophysiological themes stand out. These include protein aggregation, failure of protein homeostasis, perturbations in ion channel function, defects in DNA repair, and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. © 2011 Movement Disorder Society     

The CNTN4 c.4256C>T mutation is rare in Japanese with inherited spinocerebellar ataxia

To confirm the incidence of SCA16 in Japan, we screened DNA samples from a number of patients of ataxia of unknown etiology for the substitution. We examined a total of 323 DNA samples from Japanese patients with inherited spinocerebellar ataxia. We found no 317-base pair band in the patients with ataxia of unknown etiology. It seemed that this mutation (c.4256C>T) is rare in Japanese patients with inherited spinocerebellar ataxia. Mutations in other populations should be analyzed. Pathological examinations and molecular biological examinations are needed to confirm that this mutation is a true cause of SCA16.     

Congenital ataxia and mental retardation in three brothers

Nonprogressive congenital ataxia is a complex group of disorders caused by a variety of etiologic factors, both environmental and genetic. Hereditary forms represent a substantial part of congenital ataxias, which are difficult to classify because of their phenotypic and genetic polymorphism. Despite the advances in molecular genetics, for most nonprogressive congenital ataxia the etiology is still unknown. This report describes three sons of nonconsanguineous healthy parents, who manifested a syndrome characterized by nonprogressive ataxia, mental retardation, pyramidal signs, ocular and ocular motor anomalies, associated with severe hypoplasia of the cerebellar vermis and hemispheres on neuroimaging. All the patients have presented psychomotor developmental delay. As differential diagnosis, a comparison is made between the clinical features of these patients and the previously reported cases of nonprogressive congenital ataxia. This report represents a further example of the phenotypic and genetic heterogeneity of the syndromes with congenital ataxia.     

Hereditary ataxias-overview]

Many of autosomal dominant spinocerebellar ataxias (SCA) are now shown to result from the expansion of unstable trinucleotide repeats. In most SCAs, these repeats are present within coding sequences of the causative genes and translated into polyglutamine tracts. In this overview clinical and molecular genetic features of newly identified group of diseases in this category are briefly summarized. Expanded polyglutamine repeats are supposed to mediate some toxic effects on a certain population of neurons that result in neuronal dysfunction. The current progress in these molecular biological studies on their pathophysiology is also reviewed. In Japan, Friedreich ataxia with intoronic GAA repeat expansions has not been known. Instead, early onset ataxia with Friedreich phenotype, associated with ocular motor apraxia in childhood and with hypoalbuminemia in adult, is the predominant ataxia with Friedreich phenotype, the causative mutation of which was very recently identified.     

Parkinsonism & related disorders. Ataxias

The ataxias are a group of progressive neurodegenerative disorders with ataxia as the leading symptom. Current classifications distinguish between hereditary and non-hereditary ataxias. The hereditary ataxias are further divided into the autosomal recessive ataxias, the most frequent of which is Friedreich's ataxia, and the autosomal dominant spinocerebellar ataxias. The non-hereditary ataxias are separated into the acquired ataxias, such as alcoholic cerebellar degeneration or paraneoplastic cerebellar degeneration, and the sporadic degenerative ataxias, such as multiple system atrophy or sporadic adult onset ataxia. The causative mutations of many hereditary ataxias have recently been identified. Therapies based on the knowledge of the underlying molecular pathogenesis are available for a number of ataxia disorders.