Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia:A case report

BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

Proteolipid protein 1 gene sequencing of hereditary spastic paraplegia

PCR amplification and sequencing of whole blood DNA from an individual with hereditary spastic paraplegia, as well as family members, revealed a fragment of proteolipid protein 1 （PLP1） gene exon 1, which excluded the possibility of isomer 1 expression for this family. The fragment sequence of exon 3 and exon 5 was consistent with the proteolipid protein 1 sequence at NCBI. In the proband samples, a PLP1 point mutation in exon 4 was detected at the basic group of position 844, T→C, phenylalanine→leucine. In proband samples from a male cousin, the basic group at position 844 was C, but gene sequencing signals revealed mixed signals of T and C, indicating possible mutation at this locus. Results demonstrated that changes in PLP1 exon 4 amino acids were associated with onset of hereditary spastic paraplegia.

Verification of the Validity of the NPT Treatment in Hereditary Spastic Paraplegia: An Investigation Performed by Application of Random Matrix Theory

We have applied the Random Matrix Theory in order to examine the validity of the NPT treatment in HSP. We have investigated the pathology examining the sEMG recorded signal for about eight minutes. We have performed standard electromyographic investigations as well as we have applied the RMT method of analysis. We have investigated the sEMG signals before and after the NPT treatment. The application of a so robust method as the RMT evidences that the NPT treatment was able to induce a net improvement of the disease respect to the pathological status before NPT.

Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias

Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature

BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital.Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

The prevalence of cognitive dysfunction in the estonian population of the hereditary spastic paraplegia

The hereditary spastic paraplegias (HSPs) are neu-rodegenerative disorders of the motor system. The information about the prevalence of the cognitive dysfunction in HSP is inconsistent. The aim of the study was to describe the prevalence of cognitive dysfunction and the cognitive profiles of persons with HSP (pwHSP) compared to healthy controls. Subjects. Participating in the cognition study were 48 persons with HSP from the epidemiological study and 48 healthy controls. Of those with HSP, 81% (39/48) had pure and 19% (9/48) had complex forms. Among pwHSP, 20.8% (10/48) had pathogenic and 14.6% (7/48) had non-pathogenic mutations in the SPAST gene. There were no mutations detected in 31 persons with the SPAST gene. Methods. Neuropsychological test battery, MMSE Results. The results of the neuropsychological tests were significantly lower in persons with HSP than in the controls (Bonferroni correction, p < 0.00625). There were statistically significant differences in subtests measuring consistent long term retrieval (p < 0.001), later recall (p = 0.004) in verbal memory and symbol digit modalities (p = 0.0015). Five persons with HSP had an MMSE score of 24 or less. Conclusions. Our results demonstrate that cognitive dysfunction is present in 16.7 to 33.3% of persons with HSP, depending on the criteria applied. There was cognitive dysfunction in 30% of persons with a known pathogenic mutation in the SPAST gene. The most frequently damaged functions in HSP are consistent long term retrieval and later recall in verbal memory and symbol digit modalities tests that discriminate between controls and pwHSP with dysfunction (1.5 SD) in three or more domains. Dementia in HSP is rare.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

Hereditary spastic paraplegia type 18 （HSP18） is a complicated form ofautosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities,dysarthria,and cognitive decline. In the year 2011,HSP18,also known as Spastic Paraplegia 18 （SPG18）,was firstly identified due to a candidate gene endoplasmic reticulum lipid raft-associated protein 2 （ERLIN2） on chromosome 8pl 1.2 in one Saudis family.During the past 5 years,another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype. Here,we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2.Patient was characterized by late-onset spasticity of lower extremities without significant speech involvement or cognitive disability.

A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia

Background Hereditary spastic paraplegia （HSP） is a group of inherited neurodegenerative disorders with the shared characteristics of slowly progressive spasticity and weakness of the lower limbs. Thirteen loci for autosomal dominant HSP have been mapped. Methods A Chinese family with HSP was found in the Shandong province and Inner Mongolia Autonomous Region of China and genomic DNA of all 19 family members was isolated. After exclusion of known autosomal dominant loci, a genome wide scan and linkage analysis were performed. Results The known autosomal dominant loci of SPG3A, SPG4, SPG6, SPG8, SPG9, SPG10, SPG12, SPG13, SPG17, SPG19, SPG29, SPG31 and SPG33 were excluded by linkage analysis. The results of a genome wide scan demonstrated candidate linkage to a locus on chromosome 11 p14.1-p11.2, over an 18.88 cM interval between markers D11 S1324 and D11 S1933. A maximal, two point LOD score of 2.36 for marker D11S935 at a recombination fraction （e） of 0 and a multipoint LOD score of 2.36 for markers D11S1776, D11S1751, D11S1392, D11S4203, D11S935, D11S4083, and D11S4148 at θ=0, suggest linkage to this locus. Conclusion The HSP neuropathy in this family may represent a novel genetic entity, which will facilitate discovery of this causative gene.

A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family

Hereditary spastic paraplegia （HSP） （MIM#182600） is a group of heterogeneous neurodegenerative disorders, with 35 underlying loci recognized by the HGNC （HUGO Gene Nomenclature Committee; http：//www.gene.ucl.ac.uk/nomenclature/） and 10 identified genes （ http ： //www. gene. ucl. ac. uk/cgi-bin/nomenc lature/ searchgenes.pl plus NIPA1, last search July 2006）. The mode of inheritance may be autosomal dominant, autosomal recessive or X-linked. Among these, autosomal dominant spastic paraplegia （AD-HSP） is the most common type, accounting for 70%-80% of all families. The disease is characterized by lower limb spasticity, hyperreflexia, progressive spastic gait and an extensor plantar response. Pes cavus is one of the commonly reported foot phenotypes.

Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases

Background Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of neurodegenerative disorders of the motor system, characterized by slowly progressive spasticity and weakness of the lower extremities. This study was conducted to investigate the clinical features of hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). Methods Clinical data from five patients and thirty-five previously published case reports of HSP-TCC were analyzed retrospectively. Results Most patients were adolescents at the onset of the disease, presenting with spastic paraparesis of the lower limbs and mental impairment. Some patients also had other clinical features, including spasticity of the upper limbs, cerebellar ataxia, and sensory disturbances. Cranial MRIs of the five patients revealed an extremely thin corpus callosum, sometimes with widened cerebral sulci and ventricles, as well as with cerebellar and cerebral atrophy. Conclusion The main clinical features of HSP-TCC include slowly progressive spastic paraplegia, mental impairment during the second decade of life, and an extremely thin corpus callosum as shown on cranial MRIs.

Receptor expression-enhancing protein 1 gene （SPG31） mutations are rare in Chinese Han patients with hereditary spastic paraplegia

Hereditary spastic paraplegia （HSP）, also known as familial spastic paraparesis or Stumpell-Lorrain disease, is a large group of inherited, heterogeneous neurologic disorders caused by the degeneration of corticospinal axons. The prevalence is estimated at 3-10 cases per 100000 people in Europe, and is uncertain in other continents. Most patients have the same core features, which are characterized by spastic gait, lower limb hypertonicity, hyperreflexia, extensor-plantar responses, muscle weakness, and occasionally decreased vibration sense at the ankles, bladder dysfunction, pes cavus, or scoliosis.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Background:Although many causative genes of hereditary spastic paraplegia(HSP)have been uncovered in recent years,there are still approximately 50% of HSP patients without genetically diagnosis,especially in autosomal recessive(AR)HSP patients.Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.Methods:In this study,we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing(NGS),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA).Further functional studies were performed to identify pathogenicity of those uncertain significance variants.Results:We identified 11 mutations in HSP related genes including 7 novel mutations,including two(p.V1979_L1980delinsX,p.F2343 fs)in SPG11,two(p.T55 M,p.S308 T)in AP5Z1,one(p.S242N)in ALDH18A1,one(p.D597fs)in GBA2,and one(p.Q486X)in ATP13A2 in 8 index patients and their family members.Mutations in ALDH18A1,AP5Z1,CAPN1 and ATP13A2 genes were firstly reported in the Chinese population.Furthermore,the clinical phenotypes of the patients carrying mutations were described in detail.The mutation(p.S242 N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55 M,p.S308 T)in AP5Z1 induced lysosomal dysfunction.Conclusion:Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

Hereditary spastic paraplegia type 56:what a mouse can tell-a narrative review

Hereditary spastic paraplegia type 56(SPG56-HSP)is a rare autosomal recessive disorder caused by loss of function mutations in CYP2U1,leading to an early-onset limbs spasticity,often complicated by additional neurological or extra-neurological manifestations.Given its low prevalence,the molecular bases underlying SPG56-HSP are still poorly understood,and effective treatment options are still lacking.Recently,through the generation and characterization of the SPG56-HSP mouse model,we were able to take few important steps forward in expanding our knowledge of the molecular background underlying this complex disease.Leveraging the Cyp2u1-/-mouse model we were able to identify several new diagnostics biomarkers(vitamin B2,coenzyme Q,neopterin,and interferon-alpha),as well as to highlight the key role played by the folate pathway in SPG56-HSP pathogenesis,providing a potential treatment option.In this review,we discuss the major role played by the Cyp2u1-/-model in dissecting clinical and biological aspects of the disease,opening the way to a series of new research paths ranging from clinical trials,biomarker testing,and to the expansion of the underlying genetic and molecular,emphasizing how basic mouse model characterization could contribute to advance research in the context of rare disorders.

Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structura predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe pheno- types can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domainand the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides po- tential evidence for a possible correlation between the severity of the phenotypes of HSP with the ex- tension of the changes in the protein structures of atlastin.

A novel KIAA0196（SPG8） mutation in a Chinese family with spastic paraplegia

Hereditary spastic paraplegia （HSP） is one of the most.heterogeneous genetic neurodegenerative diseases,caused by mutations in more than 50 different genes.The eighth HSP locus,SPG8,is on chromosome 8p24.13.SPG8 is a rare autosomal dominant-HSP （AD-HSP） caused by mutations in the KIAA0196 gene,with only seven SPG8families described to date.1 Here,we described the clinical characteristics of AD-HSP caused by a novel mutation in the KIAA0196 gene in a Chinese family.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

以神经系统损伤为首发症状的2例原发性干燥综合征报道

目的·总结以神经系统损伤为首发症状的2例原发性干燥综合征(primary Sjögren's syndrome,pSS)患者的临床特点并复习相关文献。方法·对以神经系统受累为首发症状的2例pSS患者的临床表现、实验室检查结果、影像学检查结果、唇腺活检结果、治疗效果等进行总结和分析。结果·病例1,女性,自50岁起出现进行性行走不稳伴下肢远端感觉障碍,表现为痉挛步态、感觉性共济失调、传导束性感觉障碍和二便障碍;58岁起无法独立行走。实验室检查提示抗核抗体阳性(1∶1000着丝点型),抗干燥综合征抗原A(SSA)/Ro-52抗体、抗SSA/Ro-60抗体、抗着丝点抗体阳性;唇腺活检可见唾液腺组织、导管间及小叶内淋巴细胞浸润灶2个/4 mm^(2)(淋巴细胞>50个)。头颅磁共振成像可见“蛇眼征”;肌电图显示右侧腓神经运动纤维轴索损伤。在院期间予以大剂量糖皮质激素冲击、联合免疫抑制剂治疗后明显好转。3个月后可推助行器行走,日常生活基本自理。病例2,女性,自81岁起出现颈部不自主右斜,既往有轻度口干、眼干、伴膝关节疼痛1年。实验室检查提示抗SSA/Ro-52抗体、抗SSA/Ro-60抗体阳性,血红蛋白86 g/L;唇腺活检可见小唾液腺组织部分腺泡萎缩,间质内见淋巴细胞、浆细胞浸润灶2个/4 mm^(2)(淋巴细胞>50个)。周围神经电生理检查结果提示右侧正中神经传导速度减慢。经免疫抑制剂、解痉、肌松药物治疗后症状较前好转。结论·以复杂型痉挛性截瘫样表现、颈部肌张力障碍为首发症状的病例拓展了pSS的临床表型谱;临床上应注意鉴别继发于pSS的神经系统损伤与其他原发神经系统疾病;对于具有无明显原因的神经系统损伤症状的患者,应当筛查相关自身免疫抗体。

多参数MRI随访观察遗传性痉挛性截瘫5型患者脊髓微结构改变

目的评估多参数MRI随访观察遗传性痉挛性截瘫5型(SPG5)患者脊髓微结构改变的价值。方法前瞻性纳入11例接受颈胸段脊髓MR检查及痉挛性截瘫评价量表(SPRS)评分的SPG5患者,随访1年后进行第2次MR检查及SPRS评分,比较2次SPRS评分、脊髓整体结构及脊髓微结构变化。结果11例SPG5患者2次SPRS评分结果差异无统计学意义(P>0.05)。相比首次颈胸段脊髓MRI,第2次MRI显示脊髓萎缩程度加重;首次与第2次MRI所测C4右侧皮质脊髓束(CST)轴向弥散系数(AD)差异有统计学意义(t=3.987,P<0.01),C4其余参数差异均无统计学意义(P均>0.05);其余椎体脊髓白质、后索、左/右侧CST的各向异性分数(FA)、平均弥散系数(MD)、AD、径向弥散系数(RD)及T1值,以及C1~T9椎体截面积(CSA)、左右径及前后径差异均无统计学意义(P均>0.05)。第2次MRI显示颈段脊髓白质、后索及CST的FA均低于、而RD均高于首次(P均>0.05)。结论多参数MRI可用于随访观察SPG5患者脊髓微结构变化。

遗传性痉挛性截瘫5型患者脑白质微结构改变的脑白质纤维束追踪法研究

目的基于磁共振感兴趣区脑白质纤维束追踪法,探讨遗传性痉挛性截瘫5型(SPG5)患者脑白质微结构的变化特点。资料与方法前瞻性收集2019年1月—2020年12月在福建医科大学附属第一医院就诊的SPG5患者17例,通过社会公开招募性别、年龄匹配的健康对照者17名,行全脑磁共振扩散张量成像,追踪受试者双侧大脑的运动传导通路和感觉传导通路的纤维束,计算各向异性分数(FA)和平均扩散系数(MD),进行组间比较,采用Pearson相关性分析SPG5患者扩散张量成像参数与病程、疾病严重程度痉挛性截瘫评价量表及血浆27-羟基胆固醇含量的相关性。结果与对照组比较,SPG5患者在运动及感觉传导通路纤维束上FA值较低,MD值较高,差异均有统计学意义(P<0.05),延髓、放射冠及大脑皮层下白质节段二者FA值(t=-7.05~-2.01)及MD值(t=-0.25~6.50)的差异较脑桥、中脑、内囊节段的FA值(t=-4.84~1.04)及MD值(t=-1.71~4.33)大。SPG5患者扩散张量成像参数与病程、痉挛性截瘫评分量表评分及血浆27-羟基胆固醇含量均无相关性(P均>0.05)。结论SPG5患者在运动及深感觉相关的纤维束脑白质微结构呈节段性损伤趋势而非逆行性改变,白质微结构损伤程度与疾病严重程度、病程及血浆神经毒性物质含量均无相关性。

遗传性痉挛性截瘫诊断策略

遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP)是一组具有高度临床和遗传异质性的神经退行性疾病,以下肢进行性痉挛为最主要的临床特点。在临床实践中,如何对该疾病进行诊断和鉴别诊断,进一步在种类繁多的致病基因中进行HSP分型诊断,具有一定挑战性。随着基因检测技术不断发展,一方面诸多新致病基因得到克隆或重新定位,另一方面如何合理利用遗传分析辅助鉴别诊断和分型诊断,需进一步规范基因检测技术的应用策略。本文对HSP的临床特点、基因分型、诊断与鉴别诊断等进行综述。