随访十年的脊髓小脑性共济失调3型一家系研究及伦理学分析

目的 探讨随访十年的脊髓小脑性共济失调3型(SCA3)一家系的临床特征、影像学特点和基因型及其所带来的医学伦理学问题。方法 描述一家系7例患者的临床表现,对部分患者行头颅核磁共振及基因检测,结合文献复习并分析该家系中患者的临床表现、遗传特征,且进行相关的伦理学分析。结果 一家系4代21名成员中共有7例发病,以步态不稳和言语不清为突出表现,头颅MRI示小脑萎缩,其中4例患者基因检测SCA3相关基因的CAG重复数分别为76、77、76、78次,1例症状前患者为77次。结论 SCA3为一组神经系统遗传性疾病,临床特征以小脑性共济失调和构音障碍为突出表现,具有高度异质性,CAG 重复序列数目的检测对于基因诊断和症状前诊断是一种十分有效的方法。临床要严格按照医学伦理规范进行严谨的遗传检测。长期随访促进家族成员进行基因筛查,有助于发现症状前患者及促进产前诊断和优生优育。     

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.     

脊髓小脑性共济失调3型一家系报道

正1病例报告患者(先证者,Ⅳ4)男,58岁,因"渐进性步态不稳、言语含糊6年,卧床3年,抽搐2h"于2015-03-16入作者医院。患者2009年开始无明显原因出现步态不稳,言语含糊,取物不准,病程呈进行性加重。2012年开始患者行走不能,言语不清症状加重。患者自2012年开始卧床。本次入院前2h无明显诱因出现发作性肢体抽搐伴短     

脊髓小脑性共济失调6型

脊髓小脑性共济失调(SCA)6型(SCA6)为常染色体显性遗传的SCA的一种类型,与编码电压门控钙离子通道α1A亚单位(CACNL1 A4)基因3’区域三核苷酸CAG重复扩增相关,可见缓慢进展的共济失调和构音障碍：德国SCA6占常染色体显性遗传性共济失调(ADCA)家系的13％．近30％SCA6患者误诊为散发性疾病。西欧SCA6占ADCA的2％;法国罕见,仅为ADCA的1％;     

脊髓小脑性共济失调3型一家系的临床表现分析

目的 探讨1个脊髓小脑性共济失调3型(SCA3)家系中患者的临床表现,分析影响其特征、异质性及严重程度的原因。方法 采用PCR、琼脂糖凝胶电泳的方法对1个脊髓小脑性共济失调家系进行基因检测明确分型并获得等位基因内CAG三核苷酸重复扩增次数; 对比该家系中5例患者的典型症状、非典型症状,了解其临床异质性并分析产生原因。结果 确定该家系为脊髓小脑性共济失调SCA3型,发现3名表现正常的女性携带者。CAG重复次数与病程长短呈负相关(r=-0.942,P<0.05); 病程与共济失调严重程度呈正相关(r=1.000,0.913,P<0.01)。结论 该家系所有患者以明显共济失调及构音障碍为临床特征,特别是躯干及下肢的共济失调; CAG重复次数、病程及共济失调严重程度之间有明显相关性; 认知功能障碍随着疾病的进展逐渐显现; 眼肌麻痹、括约肌功能障碍或吞咽困难与CAG重复次数之间无明显关系但增加疾病持续时间; 锥体束受损及严重程度可能提示预后不良。     

遗传性脊髓小脑性共济失调一家系报道

本文报道一个遗传性脊髓小脑性共济失调（spinocerebellar ataxia．SCA）家系,观察了该家系患者的临床症状、体征及辅助检查结果,并对其中2例患者做了基因检测。我们通过复习相关文献,对该类疾病的发病机制、分类、临床特征等进行了总结以及讨论。[第一段]     

一家系4代9例脊髓小脑性共济失调临床特征与基因检测分析

目的通过对一家系4代9例脊髓小脑性共济失调(SCA)患者的临床特征和部分患者的基因测序分析,为临床诊断提供依据。方法通过先证者建立家系图谱,收集患者的发病年龄、主要症状、持续时间和死亡患者的年龄,建立该家系患者的临床特征;通过聚合酶链反应(PCR)技术检测先证者和其无症状女儿的SCA1、SCA2、SCA3、SCA6、SCA7、SCA12和齿状核-红核-苍白球-丘脑路易斯核萎缩(DRPLA)的三核苷酸重复序列的数目,确立其遗传类型。结果该家系4代9例患者,第Ⅰ代发病年龄55岁,死亡60岁;第Ⅱ代发病年龄50岁,死亡60岁;第Ⅲ代发病30～47岁,死亡60岁;第Ⅳ代发病20岁。主要症状均为走路不稳和语言含糊不清,从发病到死亡的持续时间1～30年;基因测序表明先证者SCA3相关基因的CAG重复数目20/73,其女儿为15/78;其余SCA1、SCA2、SCA6、SCA7、SCA12、DRPLA基因测序均在正常范围内。确诊为SCA3。结论基因测序可以帮助确诊SCAs和无症状患者。     

脊髓小脑性共济失调一家系的基因诊断

目的 对1个常染色体显性遗传的脊髓小脑性共济失调(SCA)家系进行基因诊断.方法 采用PCR技术,对一汉族SCA家系(包括3例患者及3位无症状成员)及50名正常对照者的SCA1 ～3基因进行检测,通过琼脂糖凝胶电泳和产物直接测序法计数等位基因内CAG三核苷酸重复次数.结果 该家系中所有成员SCA1、SCA2基因CAG三核苷酸重复次数在正常范围;3例患者SCA3 CAG重复次数分别为67、68和66次,1位无症状成员为71次.结论 该家系为SCA3,基因检测诊断出1例症状前患者.     

土家族脊髓小脑共济失调一家系报道

<正>1 病例报告患者(先证者),女,土家族,51岁。因“进行性步态不稳20余年,伴言语不清5年”入作者医院。患者于30余岁时开始出现双下肢步态不稳,有踩棉花感及踏空感,走路摇晃,不能走直线。病情进行性加重,渐出现双下肢独立行走困难,需拄杖行走。5年前出现言语笨拙,吐字不清,饮水呛咳,无吞咽困难,症状呈进行性加重。目前患者基本卧床,尚能勉强扶走,言语含混不清。病程中有多汗、记忆力下降。查体：血压125/80 mmHg,     

遗传性脊髓小脑型共济失调6型两个家系的临床特征及基因突变研究

目的 研究中国人遗传性脊髓小脑型共济失调6型(SCA6)的基因突变和临床特征。方法 应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术，检测临床诊断脊髓小脑型共济失调(SCA)的120个家系210例患者和47例散发SCA患者的SCA6基因内CAG三核苷酸重复序列，并对异常等位基因片段进行DNA测序。结果 检出2个家系(4例患者)为SCA6，阳性率为1，7％，测序证实其异常等位基因的CAG重复数目为25和26。另253例SCA患者的SCA6等位基因CAG重复数目为7-17，健康人SCA6等位基因CAG重复数目为5-16。2个家系均存在遗传早现现象，异常扩展的CAG序列呈代间稳定性。结论 从临床及基因诊断方面首次确认中国大陆存在SCA6家系；CAG过度扩增为SCA6的致病原因。     

脊髓小脑性共济失调2型的分子遗传学诊断及临床分析

目的:研究分析脊髓小脑性共济失调2型(SCA2)的分子遗传学诊断、应用以及临床表现特征。方法:对来自广西地区临床诊断为SCA的1个家系2例患者和8名"健康"家系成员,以及35名正常对照人员,通过聚合酶链式反应、琼脂糖电泳等技术检测SCA2基因位点内CAG三核苷酸重复扩增次数,并对异常等位基因片段进行DNA测序。结果:我国广西正常人群SCA2等位基因CAG重复数为20～29次,1家系中2例患者与1例症状前患者存在SCA2(CAG)n扩展突变,拷贝数分别为42、45、55次。结论:首次发现广西SCA2,利用分子遗传学分析可进行SCA2基因诊断,为症状前诊断及遗传咨询提供依据。     

Spinocerebellar ataxia type 10: Frequency of epilepsy in a large sample of Brazilian patients

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by an ATTCT repeat intronic expansion in the SCA10 gene. SCA 10 has been reported in Mexican, Brazilian, Argentinean and Venezuelan families. Its phenotype is overall characterized by cerebellar ataxia and epilepsy. Interestingly, Brazilian patients reported so far showed pure cerebellar ataxia, without epilepsy. Here, authors provide a systematic analysis of the presence, frequency and electroencephalographic presentation of epilepsy among 80 SCA10 patients from 10 Brazilian families. Overall, the frequency of epilepsy was considered rare, been found in 3.75 % of the cases while this finding in populations from other geographic areas reaches 60% of SCA10 cases. © 2010 Movement Disorder Society     

Clinical,Imaging, and Laboratory Markers of Premanifest Spinocerebellar Ataxia 1, 2, 3, and 6: A Systematic Review

Background and PurposePremanifest mutation carriers with spinocerebellar ataxia (SCA) can exhibit subtle abnormalities before developing ataxia. We summarized the preataxic manifestations of SCA1, -2, -3, and -6, and their associations with ataxia onset.MethodsWe included studies of the premanifest carriers of SCA published between January 1998 and December 2019 identified in Scopus and PubMed by searching for terms including ‘spinocerebellar ataxia’ and several synonyms of ‘preataxic manifestation’. We systematically reviewed the results obtained in studies categorized based on clinical, imaging, and laboratory markers.ResultsWe finally performed a qualitative analysis of 48 papers. Common preataxic manifestations appearing in multiple SCA subtypes were muscle cramps, abnormal muscle reflexes, instability in gait and posture, lower Composite Cerebellar Functional Severity scores, abnormalities in video-oculography and transcranial magnetic stimulation, and gray-matter loss and volume reduction in the brainstem and cerebellar structures. Also, decreased sensory amplitudes in nerve conduction studies were observed in SCA2. Eotaxin and neurofilament light-chain levels were revealed as sensitive blood biomarkers in SCA3. Concerning potential predictive markers, hyporeflexia and abnormalities of somatosensory evoked potentials showed correlations with the time to ataxia onset in SCA2 carriers. However, no longitudinal data were found for the other SCA gene carriers.ConclusionsOur results suggest that preataxic manifestations vary among SCA1, -2, -3, and -6, with some subtypes sharing specific features. Combining various markers into a standardized index for premanifest carriers may be useful for early screening and assessing the risk of disease progression in SCA carriers.     

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

Background

More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion.

Objective

The objective of this study was to confirm a novel SCA subtype caused by CAG expansion.

Methods

We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells.

Results

We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5–6 in controls), whereas the number of 3′ pure CAG repeats was up to 32 to 87 (4–16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats.

Conclusions

This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis

INTRODUCTION: The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability. MATERIALS AND METHODS: We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated. RESULTS: Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population. CONCLUSIONS: This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.