遗传性痉挛性截瘫伴薄胼胝体6例报道并文献复习

目的探讨遗传性痉挛性截瘫伴薄胼胝体(HSP-TCC)的发病机制、临床特点、影像学表现及预后。方法分析6例HSP-TCC患者的临床及影像学表现,结合文献复习总结其临床特征。结果 6例患者均青少年起病,表现为痉挛步态,腱反射亢进,病理征阳性,2例有共济失调。患者均无感觉障碍及大小便障碍。全部患者头颅MRI显示胼胝体变薄。结论 HSP-TCC作为复杂型遗传性痉挛性截瘫(HSP)的一种,临床上以双下肢痉挛性截瘫和薄胼胝体为特征,发病机制尚不清楚,预后较差。     

遗传性痉挛性截瘫合并胼胝体发育不良伴SPG11基因突变1例报道并文献复习

<正>遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP)是一组具有高度临床特征和遗传异质性的神经系统变性疾病~([1]),分为单纯型及复杂型。遗传性痉挛性截瘫伴胼胝体发育不良(hereditary spastic paraplegia with thin corpus callosum,HSP-TCC)属于复杂型HSP,在临床上极为罕见,至今国内外     

遗传性痉挛性截瘫伴胼胝体发育不良的遗传学研究进展

遗传性痉挛性截瘫伴胼胝体发育不良（HSP-TCC）是复杂型HSP的一种,临床特点为进行性双下肢痉挛伴胼胝体发育不良,多儿童及青少年发病,常伴智能障碍。HSP-TCC具有高度的遗传异质性,病理提示皮质脊髓束变性。目前已发现至少19个疾病基因,主要包括：SPG1、SPG11、SPG15、SPG21、SPG35、SPG44、PG47、SPG54、SPG56等。该文就近年来有关该病的遗传学研究进展进行了综述,以期有助于该病的鉴别与诊断。     

遗传性痉挛性截瘫的病理、遗传学、发病机制和临床的研究进展

遗传性痉挛性截瘫(HSP或SPG),又称为Str櫣mpell-Lor-rain病,是一种具有临床及遗传异质性的神经系统遗传病,表现为缓慢进展的双下肢无力及痉挛性截瘫。根据HSP临床特征的不同分为两型,即单纯型及复杂型。单纯型HSP表现为逐渐进展的双下肢痉挛、步态不稳、键反射亢进,可以合并膀胱括约肌功能障碍;复杂型HSP除了上述临床表现外还可伴有智力障碍、锥体外系症状、共济失调、癫癎、白内障、视神经萎缩、视网膜变性、鱼鳞病及周围神经病等;根据遗传方式不同HSP可分为常染色体显性遗传(AD)、常染色体隐性遗传(AR)和X-连锁隐性遗传(XR),其…     

遗传性痉挛性截瘫的分子遗传学进展

遗传性痉挛性截瘫 (hereditaryspasticparaplegia ,HSP或SPG) ,又称Str櫣ｍｐｅｌｌ Lorrain病 ,是一组具有明显临床和遗传异质性的神经系统变性疾病 ,按临床表现可分为单纯型和复杂型 ,单纯型只表现为进行性双下肢肌张力增高和无力 ,合并脊髓外损害 ,如肌肉萎缩、精神发育迟滞、共济失调、多发性神经病、视神经萎缩、视网膜色素变性、耳聋、锥体外系等症状的称为复杂型 ;按遗传方式分为常染色体显性遗传(AD)、常染色体隐性遗传 (AR)和X 连锁隐性遗传 (XR)。据统计 ,HSP的患病率为 2 0 / 1 0万至 9 6/ 1 0万[1 ] 。近年来 ,本病的…     

遗传性痉挛性截瘫的临床和遗传特点

目的：探讨遗传性痉挛性截瘫的临床和遗传特点。方法：对39个家系113例患者的临床资料进行回顾性分析。结果：男：女为1：1.17，发病年龄2-58岁，平均21.4岁，30例以前发病占81.7％。有家族史者占89.4％，多呈常染色体显性遗传。近亲结婚家系占28.2％。单纯型24例，复杂型89例。双下肢肌力下降占65.5％，肌张力增高和腱反射亢进均为96.5％，病理征阳性68.1％。合并症中共济失调占46.9％，肌萎缩占32.7％，痴呆占18.6％。结论：本组遗传性痉挛性截瘫患者多于青少年或青年发病，女性多于男性，复杂型较单纯型多见，遗传方式以常染色体显性遗传多见，近亲结婚明显增加该病的发生。     

贵州少数民族遗传性痉挛性截瘫3家系临床特点分析

目的探讨贵州地区已发现的少数民族(布衣、苗、彝)遗传性痉挛性截瘫(HSP)临床表现特征。方法对3个来自贵州不同少数民族常染色体显性遗传(AD)HSP家系内患者及部分成员临床资料进行详细回顾分析。结果 3个家系均为常染色体显性遗传;现证者男性明显多于女性(11∶3);复杂型比例较高,占71.4%(10/14),且最常见的合并症为共济失调(7/10);遗传早现现象明显(2/3);HSP家系中PD的发生率较高(2/3)。结论贵州地区少数民族HSP复杂型比例比国外文献报道高,最常见的合并症是共济失调,遗传早现明显。     

遗传性痉挛性截瘫SPG4和SPG3A基因突变和多态分析

目的 筛查并分析遗传性痉挛性截瘫(HSP)SPG4和SPG3A基因突变,了解中国人群这2个基因的突变特点.方法 联合应用变性高效液相色谱分析(DHPLC)和DNA序列分析方法对24例常染色体显性遗传的HSP(AD-HSP)家系的先证者和32例散发性HSP患者进行SPG4和SPG3A基因突变筛查,对24例AD-HSP家系的先证者进一步直接测序筛查这2个基因的突变.结果 在1个AD-HSP家系中发现1个位于SPG4基因上的新犁突变1616+1g→t杂合突变.在此家系中,共发现了3例现症患者和2例症状前患者.本组病例未检出SPG3A基因突变.此外,共发现了8种新的SPG4多态和3种新的SPG3A多态.结论 本组检测结果 丰富了SPG4和SPG3A基因的突变和多态库.这2个基因突变在本组病例中较少见,需要继续分析其他基因.     

遗传性痉挛性截瘫

遗传性痉挛性截瘫 (HSPS) ,也称作Strumpell -Lorrain病 ,是一组罕见的以显著的临床及遗传异质性为特征的疾病。自 1883年被初次描述以来已发现了多种的临床形式。单纯型表现为反射活跃 ,Babinski征 ,双下肢的痉挛及运动缺损通常伴有弓行足 ,深感觉损害 ,括约肌障碍 ,有时有上肢辩距障碍。其他形式称为复杂型 ,指表现为一种或几种神经或神经外特征。现已弄清其他神经变性疾病也可存在与复杂型HSP相似的表现型 ,如成人Friedreich’s共济失调和肌萎缩性侧索硬化症 (ALS) ,故这些疾病的分类不仅要靠临床而且要依赖遗传模式 (常染色体显性…     

晚发型脊髓小脑性共济失调3型1例报告

正脊髓小脑性共济失调(SCA)是具有临床和遗传异质性的神经系统疾病,多呈常染色体显性遗传,主要表现为慢性进行性加重的共济失调、构音障碍及眼球运动障碍等。现报道的SCA亚型多达40种,其发病年龄及临床症状多相互重叠~([1]),仅依据临床特征及影像学检查明确分型较为困难,基因检测有助于进一步明确诊断。本文报道1例确诊为晚发型SCA3型(SCA3)的病例如下。1病例男,66岁。因"双下肢走路不稳10年,加重半年"     

Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.     

Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families

Hereditary spastic paraplegia (HSP) type 15 is an autosomal recessive (AR) form of complicated HSP mainly characterized by slowly progressive spastic paraplegia, mental retardation, intellectual deterioration, maculopathy, distal amyotrophy, and mild cerebellar signs that has been associated with the Kjellin syndrome. The locus for this form of HSP, designated SPG15, was mapped to an interval of 19 cM on chromosome 14q22-q24 in two Irish families. We performed a clinical-genetic study of this form of HSP on 147 individuals (64 of whom were affected) from 20 families with AR-HSP. A genome-wide scan was performed in three large consanguineous families of Arab origin after exclusion of linkage to several known loci for AR-HSP (SPG5, SPG7, SPG21, SPG24, SPG28, and SPG30). The 17 other AR-HSP families were tested for linkage to the SPG15 locus. Only the three large consanguineous families showed evidence of linkage to the SPG15 locus (2.4 > Z (max) > 4.3). Recombinations in these families reduced the candidate region from approximately 16 to approximately 5 Mbases. Among the approximately 50 genes assigned to this locus, two were good candidates by their functions (GPHN and SLC8A3), but their coding exons and untranslated regions (UTRs) were excluded by direct sequencing. Patients had spastic paraplegia associated with cognitive impairment, mild cerebellar signs, and axonal neuropathy, as well as a thin corpus callosum in one family. The ages at onset ranged from 10 to 19 years. Our study highlights the phenotypic heterogeneity of SPG15 in which mental retardation or cognitive deterioration, but not all other signs of Kjellin syndrome, are associated with HSP and significantly reduces the SPG15 locus.     

Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The major features of HSP are a marked phenotypic variability both among and within families and an extended genetic heterogeneity. More than 20 HSP loci and 10 spastic paraplegia genes ( SPG) have been identified to date, including the genes responsible for the two most frequent forms of autosomal dominant spastic paraplegia (AD-HSP), encoding spastin ( SPG4) and atlastin ( SPG3A), respectively. To date, only eight mutations have been described in the atlastin gene, which was reported to account for about 10% of all AD-HSP families. We investigated 15 German and French AD-HSP families, including the 3 large pedigrees that allowed the mapping and subsequent refinement of the SPG3A locus. Three novel mutations were found in exons 4, 9, and 12 of the atlastin gene and the common R239C mutation located in exon 7 was confirmed in a 7th family of European origin. Overall, the comparison of the clinical data for all SPG3A-HSP families reported to date failed to reveal any genotype/phenotype correlation as demonstrated for other forms of AD-HSP. However, it confirmed the early onset of this form of HSP, which was observed in almost all affected individuals with a mutation in the atlastin gene.     

Pure adult-onset Spastic Paraplegia caused by a novel mutation in the KIAA0196 (SPG8) gene

SPG8 is a rare autosomal dominant hereditary spastic paraplegia (AD-HSP), with only six SPG8 families described so far. Our purpose was to screen for KIAA0196 (SPG8) mutations in AD-HSP patients and to investigate their phenotype. Extensive family investigation was performed after positive KIAA0196 mutation analysis, which was part of an on-going mutation screening effort in AD-HSP patients. A novel pathogenic KIAA0196 mutation p.(Gly696Ala) was identified in two AD-HSP patients, who subsequently were shown to belong to a single large Dutch pedigree with more than 10 affected family members. The phenotype consisted of a pure HSP with ages at onset between 20 and 60 years, distally reduced vibration sense in the legs in all, and urinary urgency in seven out of 10 patients. Frequent features were exercise- or emotion-induced increase of spasticity and gait problems and chronic nonspecific lower back and joint pains. We have identified a fourth pathogenic KIAA0196 mutation in a Dutch HSP-family, the seventh family worldwide, with a less severe clinical course than described before.     

Phenotype of AD-HSP due to mutations in the SPAST gene: comparison with AD-HSP without mutations

BACKGROUND: "Pure" autosomal dominant hereditary spastic paraparesis (AD-HSP) is clinically and genetically heterogeneous. There are at least seven genetic loci with varying ages at onset and disability. The SPAST gene at the SPG4 locus on chromosome 2p is the major disease gene for AD-HSP. OBJECTIVES: To investigate whether there are distinct clinical features among families with AD-HSP due to SPAST mutations compared with families excluded from SPG4. METHODS: Nineteen families with "pure" AD-HSP were identified, and the clinical features of family members were compared using a standard protocol. With use of genetic studies, the families were divided into two groups for comparison: those with mutations in SPAST, the "mutation-positive" group, and those excluded from SPG4 on the basis of linkage studies, the "SPG4-excluded" group. RESULTS: Twenty-nine individuals from four families had mutations in SPAST, whereas 22 individuals from three families comprised the SPG4-excluded group; in 11 families, the pattern of linkage was unknown. In the one remaining family, no mutations were found despite strong linkage to SPG4. Different mutations were identified in the four SPAST pedigrees, but the clinical picture was similar in each. Comparison of the mutation-positive group with the SPG4-excluded group revealed an older age at onset (p = 0.03), more disability (p = 0.001), more rapidly progressive paraparesis (p = 0.044), and more cognitive impairment (p = 0.024) among affected individuals with SPAST mutations, not confounded by disease duration. CONCLUSION: Despite different mutations, SPAST families have a similar phenotype that can be distinguished from other genetic groups.     

The high prevalence of hereditary spastic paraplegia in Sardinia, insular Italy

The few epidemiological studies conducted to date on the heterogeneous group of hereditary spastic paraplegias (HSPs) indicate a prevalence of 1.27–12.1 per 100,000. This study aims to explore the epidemiological, clinical, and genetic variability of HSPs among Sardinians, a population of peculiar ethnicity.A population-based prevalence study was performed in north-western Sardinia between January 2000 and December 2010. Multiple sources were used for case ascertainment. Familial and sporadic cases were diagnosed according to generally accepted criteria, and clinical diagnoses were validated by expert neurological examination. Clinical data and pedigree information were recorded and blood samples drawn for genetic testing.Sixty-seven HSP patients were included in the study: 59 belonged to 11 families with autosomal dominant transmission (AD-HSP), three cases were from two unrelated autosomal recessive families, and the remaining five cases were apparently sporadic. On 31 December 2010, the total crude prevalence was 19.9 per 100,000 (95 % CI 18.4–21.4), while the crude prevalence of AD-HSP was 17.5 (24.4 M, 15.7 F; M:F ratio 1.55). The mean age at examination was 48.4 years, and the mean age at onset of HSP was 36.6 years. A molecular diagnosis was obtained in 82.1 % of the cases (52 cases with mutations in SPAST/SPG4, two in SPG7, and one in SPG11).The prevalence of HSP among Sardinians is high compared with other Western European populations. The multiple search strategy used in this study and the specific socio-demographic characteristics of Sardinians may account for this finding.     

Chinese patients with Machado-Joseph disease presenting with complicated hereditary spastic paraplegia

Background and purpose:  The clinical overlap between Machado-Joseph disease (MJD) and autosomal dominant complicated hereditary spastic paraplegia (AD-HSP) is extensive and the differentiation between them can be difficult on clinical ground. However, patients are seeking the right diagnosis and it is important for neurologists to distinguish them in the early stage.
Methods:  In recent 10 years, we have recruited and followed-up three families which were initially diagnosed as complicated AD-HSP based on the clinical criteria. Mutation analyses of SPG4 , SPG3A and ATXN3 were performed in the index cases.
Results:  No mutations on SPG4 and SPG3A were found. Mutation analysis of ATXN3 showed that these cases have one expanded allele and one normal allele. The copy numbers of CAG repeats were 80/28, 86/28 and 83/33, respectively.
Conclusions:  The molecular diagnosis confirmed that they were MJD patients though they had been misdiagnosed as complicated AD-HSP for many years. The copy numbers of expanded allele were more than 80 and the copy numbers of normal allele were more than 27, which could somewhat explain the earlier onset age of these cases and the anticipation of the pedigrees. Our data emphasize the necessity to perform the mutation analysis of ATXN3 in clinically diagnosed complicated AD-HSP patients.