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。     

遗传性痉挛性截瘫伴胼胝体发育不良的临床分析及文献回顾

目的:分析遗传性痉挛性截瘫伴胼胝体发育不良(HSP-TCC)的临床特点,以提高对此病的认识。方法:结合文献复习并报告1 例HSP-TCC患者的临床和影像学表现。结果:本例HSP-TCC的双亲为表兄妹婚配,临床以缓慢进行性痉挛性截瘫为主要表现,MRI 示胼胝体发育不良和脑室周围白质疏松,侧脑室对称轻度扩大;胸腰髓明显变细,但脊髓本身未见明显异常信号。结论:建议凡家族性痉挛性截瘫患者均应常规行MRI检查,以判定是否并有胼胝体发育不良,可提高本病的诊断率。     

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。     

遗传性痉挛性截瘫一家系临床及spastin基因突变的特点

目的 探讨遗传性痉挛性截瘫(SPG)一家系临床及基因突变的特点.方法 回顾性分析一个SPG家系的临床资料.结果 该家系内5代共有5例SPG患者,各代均有发病.3例存活患者均为女性,发病年龄16 ～21岁,平均18.3岁;病程11 -58年,平均33.3年;3例患者临床表现为缓慢进展的双下肢无力,下肢肌张力明显增高.基因检测显示3例患者spastin基因c.1098+1～2gt→ctcaga突变,家系中正常成员未见该变异.结论 该SPG家系的遗传方式为常染色体显性,临床表现为单纯性SPG,为spastin基因c.1098+1 ～ 2gt→ctcaga突变所致.     

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六例的临床特征与maspardin基因突变分析

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）是一种常染色体隐性（AR）遗传的复杂型HSP，临床极为罕见，青少年发病，表现为缓慢进展的痉挛性截瘫伴痴呆，晚期可出现肌萎缩、小脑及锥体外系症状等，头部磁共振成像（MRI）示胼胝体发育不良和脑萎缩，多见于日本。Mast综合征也是一种AR遗传的复杂型HSP，儿童或青少年发病，     

遗传性痉挛性截瘫中Atlastin基因和Nipa1基因同时突变一家系分析

目的通过分析遗传性痉挛性截瘫一家系中的基因突变，探讨此家系中两种基因突变同时发生的情况。方法应用ABD100遗传分析仪对该家系成员进行DNA测序，进行SPG3A／Atlastin和SPG6／Nipa1基因突变分析。结果遗传分析显示家系中先证者（Ⅱ2）和其女儿（Ⅲ1）既是SPG3A／Atlastin（SPG3A P344L）基因突变杂合体又是SPG6／Nipa1（SPG6 T100A）基因突变的杂合体。先证者的双亲均无SPG3A／Atlastin基因突变，但其父是一个携有SPG6／Nipa1（SPG6 T100A）基因突变的杂合体。结论该家系患者同时存在SPG3A/Atlastin和SPG6/Nipa1两种基因突变，其中SPG3AZ/Atlastin为新产生的非遗传突变。     

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spastin、atlastin和paraplegin基因突变分析

目的探讨遗传性痉挛性截瘫(HSP)spastin、atlastin和parap legin基因的突变特点。方法应用聚合酶链反应-单链构象多态性(PCR-SSCP)结合DNA序列分析方法对24个常染色体显性遗传HSP家系和14例散发患者进行spastin基因和atlastin基因突变分析;对12个常染色体隐性遗传HSP家系和14例散发患者进行parap legin基因突变分析。结果在5个不同的常染色体显性遗传HSP家系中发现4个spastin基因新突变(1223 insCTCA、1258T→A,1293A→G和1668delCTA),在2例散发患者中发现2个spastin基因多态(IVS1-31C→G和IVS2-47A→G);在常染色体显性遗传HSP家系和散发患者中未发现atlastin基因突变或多态;在常染色体隐性遗传HSP家系和散发患者中未发现致病突变,仅在2例散发患者中发现2个parap legin基因多态(2063G→A及2066G→A)。结论我国遗传性痉挛性截瘫患者中spastin基因突变较常见,atlastin和parap legin基因的突变率可能较低。     

贵州部分少数民族遗传性痉挛性截瘫Spastin基因突变研究

目的筛查及分析遗传性痉挛性截瘫(HSP)Spastin基因突变,了解贵州地区少数民族(彝族、布衣族、苗族)Spastin基因突变特点。方法应用PCR产物直接DNA测序法,对9例HSP患者(包括3个家系中7例现证者和2例散发患者)Spastin基因1-17号外显子进行突变筛查;被发现存在突变的外显子,其次行家系内其他成员相对应外显子的筛查。结果在9例HSP患者中发现家系3两例患者(Ⅴ24、Ⅴ25)的Spastin基因第4号外显子同一位点上发生错义突变c.847C>T,其他参与抽血的亲属均无该位点突变,推测该位点的突变为一多态。另外的突变位点均位于外显子序列前后的内含子区域。结论此次贵州地区部分少数民族spastin基因突变率低,与国内文献报道的汉族人群不同。     

Novel mutations of the SPG11 gene in hereditary spastic paraplegia with thin corpus callosum

BACKGROUND: Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a clinically and genetically heterogeneous neurodegenerative disorder with genetic linkage to multi-loci. Recently pathogenic mutations in the KIAA1840 (now named SPG11) for SPG11, the major HSP-TCC locus, were identified; at least 42 different mutations have been detected. OBJECTIVE: To study the clinical features and identify the SPG11 gene mutations in Chinese patients with HSP-TCC. METHODS: Three kindreds with an autosomal recessive HSP-TCC and 5 cases with sporadic HSP-TCC in Chinese Hans were recruited. Detailed clinical history, neurological examination, MRI, electromyography, Mini Mental State Examination (MMSE), Spastic Paraplegia Rating Scale (SPRS) were presented. DNA samples of the 8 families were collected and mutation analysis of SPG11 gene was carried out by direct DNA sequencing. RESULTS: Except for one patient whose age at onset was 3 years old, 10 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain MRI. We identified 10 novel and one known mutations in our 8 HSP-TCC families, which were two nonsense mutations (c.5977C>T/p.Q1993X, c.4668T>A/p.Y1556X), three small deletions (c.6898_6899delCT/p.L2300AfsX2338, c.3719_3720delTA/p.I1240VfsX263, c.733_734delAT/p.M245VfsX246), four small insertions (c.7088_7089insATTA/p.Y2363X, c.2163_2164insT/p.I722YfsX731, c.7101_7102insT/p.K2368X, c.6790_6791insC/p.L2264PfsX2339), one deletion/insertion (c.654_655delinsG/p.S218RfsX219), and one splice mutation (c.7151+4_7151+7delAGTA/p.K2384fsX2386). Each family has a different mutation and all the mutations are predicted to cause early protein truncation. CONCLUSION: This study widens the mutation spectrum of the SPG11 gene and the mutations in the SPG11 gene are also the major causative gene for HSP-TCC in the Chinese Hans. Screening of the whole gene is recommended in clinical practice.     

SPG11: a consistent clinical phenotype in a family with homozygous Spatacsin truncating mutation

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Here, we describe clinical and genetic features in an Italian family affected by autosomal recessive HSP (ARHSP) with mental impairment and thin corpus callosum (TCC). In both affected subjects, genetic analysis revealed the presence of a homozygous small deletion (733_734delAT) leading to a frameshift (M245VfsX) within the coding region of SPG11 gene, encoding spatacsin. This finding is the first independent confirmation that spatacsin loss of function mutations cause ARHPS-TCC. Roberto Del Bo and Alessio Di Fonzo, These two authors equally contributed to the present work.     

Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis

Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.     

Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia

Mutations in the SPG4 gene are the most common causes of hereditary spastic paraplegia (HSP) accounting for up to 40% of autosomal dominant (AD) forms and 12–18% of sporadic cases. The phenotype associated with HSP due to mutations in the SPG4 gene tends to be pure. There is increasing evidence, however, of patients with complicated forms of spastic paraplegia in which SPG4 mutations were identified. A cohort of 38 unrelated Italian patients with spastic paraplegia, of which 24 had a clear dominant inheritance and 14 were apparently sporadic, were screened for mutations in the SPG4 gene.We identified 11 different mutations, six of which were novel (p.Glu143GlyfsX8, p.Tyr415X, p.Asp548Asn, c.1656_1664delinsTGACCT, c.1688-3C>G and c.*2G>T) and two exon deletions previously reported. The overall rate of SPG4 gene mutation in our patients was 36.8% (14/38); in AD-HSP we observed a mutation frequency of 45.8% (11/24), in sporadic cases the frequency was 21.4% (3/14). Furthermore, we found a mutational rate of 22.2% (2/9) and 41.4% (12/29) in the complicated and pure forms, respectively. The results underlie the importance of genetic testing in all affected individuals.     

Novel mutations c.[5121_5122insAG]+[6859C>T] of the SPG11 gene associated with cerebellum hypometabolism in a Chinese case of hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegia (HSP) is a very heterogeneous disease, both genetically and clinically. To date, approximately 52 loci and 31 genes have been reported to be involved in the causality of HSP. The pattern of inheritance of the disease can be autosomal dominant, autosomal recessive, or X-linked recessive. Autosomal recessive HSP with thin corpus callosum (ARHSP-TCC) is one form of this disease, and a recessive gene, SPG11, is responsible for 41–77% of all ARHSP-TCC cases. SPG11 encodes the protein SPATACSIN, which is most prominently expressed in the cerebellum. However, little is known about its function. Despite diverse clinical presentations, diffuse hypometabolism in the cerebellum has not been reported previously. We have identified an HSP-TCC patient that presented with prominent intellectual disability rather than spasticity. ¹⁸Fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) examination showed diffuse hypometabolism in both cerebella. Mutation screening of the SPG11 gene using Sanger sequencing identified the novel compound heterozygous mutation c.[5121_5122insAG]+[6859C>T] (p.[I1708RfsX2]+[Q2287X]) in the patient. The mother bears the c.5121_5122insAG mutation, which results in a frameshift and is predicted to truncate the 735 amino acids from the C-terminus, and the father carries the c.6859C>T mutation, which terminates the 157 amino acids from the C-terminus. Therefore, these mutations may result in the loss of function of wild-type SPATACSIN. Our results suggest that SPATACSIN may be involved in cerebella metabolism, and the novel mutations provide more data for the mutational spectrum of this gene, which will aid in the development of quick and accurate genetic diagnostic tools for this disease.     

Identification of novel SPG11 mutations in a cohort of Chinese families with hereditary spastic paraplegia

Aim of the study: To investigate the mutation frequency of SPG11, SPG15, SPG5 and SPG7 in China.

Materials and methods: We have scanned the whole exons of KIAA1840, ZFYVE26, SPG7 and CYP7B1 genes in a group of 36 unrelated Chinese ARHSP families.

Results: SPG11 mutations were found in 33.33% (12/36) of ARHSP patients in our study, and no mutation was identified in SPG15, SPG5 or SPG7 genes. Among the SPG11 mutations detected, c.1755_1758delAGCA/p. P585PfsX623, c.29832984delTA/p.L934LfsX1010, c.1845_1848delGTCT/p.F617Lfs*5, c.6478+1G>T and c.3662_3665delTCAA/p.I1221RfsX1230 were novel mutations, they all introduced premature termination codons which were predicted to leading to the absence of the spastacsin protein in the patients' cells. All the SPG11 patients in our study presented with spastic paraparesis and/or mental impairment at initial time, and most patients showed thin corpus callosum (TCC) and white matter abnormalities (WMA) in brain MRI. After years' duration, they gradually manifested with dysarthria, dysphagia, peripheral neuropathy, amyotrophy, skeletal deformity, cerebellar signs, ophthalmoplegia, decreased vision, sphincter disturbance and tremor.

Conclusions: SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare. The core symptoms of Chinese SPG11 patients showed no difference when compared to SPG11 in western countries, and clinical heterogeneity also existed in our SPG11 patients. We suggested that ARHSP patients with mental impairment, especially combined with TCC, should be excluded SPG11 first in China.     

Two novel mutations in the Spastin gene of Chinese patients with hereditary spastic paraplegia

Background and purpose: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases. Mutations in the spastin (SPG4) gene are responsible for approximately 40% of autosomal dominant HSP (AD‐HSP) and 6.5–18% of sporadic cases. Methods: Spastin mutations were screened in 11 AD‐HSP families and 11 sporadic cases by direct sequencing and MLPA assay. Novel mutations were detected in 100 healthy controls by PCR‐RFLP. Results: We identified seven different spastin mutations in five probands and one sporadic patient. Two of seven mutations were novel. The c.458delT was a pathogenic mutation, but the effect of c.1724 G>T remained unknown. Conclusions: This study allowed us to estimate the frequency of the SPG4 mutations in Chinese at 45% (5/11) in families with AD‐HSP and 9% (1/11) in sporadic cases. In addition, our data showed p.T614I was not associated with congenital arachnoid cysts.     

Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13–15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.Electronic Supplementary Material  Supplementary material is available for this article at     

Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia

BACKGROUND: Hereditary spastic paraplegia (HSP), a genetically and clinically heterogeneous group of neurodegenerative disorders, is characterized by progressive lower limb weakness and spasticity. Among the 8 loci associated with the autosomal dominant uncomplicated HSP (AD-HSP), the spastin (SPG4) and atlastin (SPG3A) genes have been known to account for approximately 40% and 10% of all cases, respectively. OBJECTIVE: To investigate the contribution of these 2 genes in the occurrence of HSP in Korean patients. DESIGN: Clinical and genetic study. SETTING: Tertiary care center. PATIENTS: Eighteen patients with uncomplicated HSP (11 AD and 7 sporadic) underwent screening for gene mutation. MAIN OUTCOME MEASURES: Mutations in the SPG4 and SPG3A genes as detected by direct sequencing of all coding exons and flanking intronic sequences. RESULTS: We identified 8 different SPG4 mutations, 7 of which have not been reported elsewhere. Among the detected mutations were 3 missense mutations, 2 in-frame deletions, 2 frameshift mutations, and 1 splice-site mutation. No mutation was found in the SPG3A gene. CONCLUSION: Compared with previous studies, a higher frequency of SPG4 gene mutations in AD-HSP (7/11; 64%) was observed, suggesting that a mutation analysis for the SPG4 gene might be helpful for molecular diagnosis of AD-HSP in Korean patients.     

Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity

OBJECTIVE: To perform a clinical and genetic study of Tunisian families with autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). DESIGN: Linkage studies and mutation screening. SETTING: Reference Center for Neurogenetics in South and Center Tunisia. PARTICIPANTS: Seventy-three subjects from 33 "apparently" unrelated Tunisian families with AR HSP. MAIN OUTCOME MEASURES: Families with AR HSP-TCC were subsequently tested for linkage to the corresponding loci using microsatellite markers from the candidate intervals, followed by direct sequencing of the KIAA1840 gene in families linked to SPG11. RESULTS: We identified 8 Tunisian families (8 of 33 [24%]), including 19 affected patients, fulfilling the clinical criteria for HSP-TCC. In 7 families, linkage to either SPG11 (62.5%) or SPG15 (25%) was suggested by haplotype reconstruction and positive logarithm of odds score values for microsatellite markers. The identification of 2 recurrent mutations (R2034X and M245VfsX) in the SPG11 gene in 5 families validated the linkage results. The neurological and radiological findings in SPG11 and SPG15 patients were relatively similar. The remaining family, characterized by an earlier age at onset and the presence of cataracts, was excluded for linkage to the 6 known loci, suggesting further genetic heterogeneity. CONCLUSIONS: Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity, but at least another genetic form with unique clinical features exists.