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 as...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.展开更多
Background: Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts f or approximately 10%to 15%of all autosomal dominant heredi...Background: Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts f or approximately 10%to 15%of all autosomal dominant hereditary spastic paraple gia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established. Objective: To describe a kindred wit h an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene. Patients: Complete neurological examination and genetic anal ysis were performed on 6 affected members of a small African American kindred. L inkage analysis to genetic markers near autosomal dominant hereditary spastic pa raplegia loci on chromosomes 2p and 14q was performed. The coding sequence of th e SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal contro ls. Results: Every affected individual had signs of uncomplicated spastic parapa resis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis sugg ested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene r evealed a missense mutation C635T, predicted to result in a threonine to isoleuc ine substitution at codon 156. Analysis of 200 normal chromosomes did not identi fy the same change in healthy subjects. Conclusion: We report a novel muta tion in the SPG3A gene in an African American family with an infantile onset of auto somal dominant hereditary spastic paraplegia.展开更多
Mutations in the SPG3A gene cause a form of pure, earlyonset autosomal dominant hereditary spastic paraplegia linked to chromosome 14q. The encoded protein, atlastin, is a putative member of the dynamin superfamily of...Mutations in the SPG3A gene cause a form of pure, earlyonset autosomal dominant hereditary spastic paraplegia linked to chromosome 14q. The encoded protein, atlastin, is a putative member of the dynamin superfamily of large GTPases involved in cellular trafficking patterns. We report a new atlastin mutation causing spastic paraplegia in association with axonal neuropathy in an Italian family.展开更多
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....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.展开更多
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...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.展开更多
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 (S...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.展开更多
Background:The hereditary spastic paraplegias(HSPs)are a group of clinically and genetically heterogeneous disorders.Approximately 10% of the autosomal dominant(AD)HSPs(ADHSPs)have the spastic paraplegia 3A(SPG3A)geno...Background:The hereditary spastic paraplegias(HSPs)are a group of clinically and genetically heterogeneous disorders.Approximately 10% of the autosomal dominant(AD)HSPs(ADHSPs)have the spastic paraplegia 3A(SPG3A)genotype which is caused by ATL1 gene mutations.Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear.The study aims to investigate the genotypephenotype correlation in SPG3A patients.Methods:We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.Results:Most HSPs-SPG3A patients exhibited an early age at onset(AAO)of<10 years old,and showed an autosomal dominant pure spastic paraplegia.We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes,with distal atrophy being the most common complicated symptom.The AAO of each mutation group was not statistically significant(P>0.05).The mutational spectrum associated with ATL1 gene mutation is wide,and most mutations are missense mutations,but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.Conclusions:Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients.We also find that exons 4,7,8 and 12 are mutation hotspots in ATL1 gene.展开更多
文摘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.
文摘Background: Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts f or approximately 10%to 15%of all autosomal dominant hereditary spastic paraple gia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established. Objective: To describe a kindred wit h an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene. Patients: Complete neurological examination and genetic anal ysis were performed on 6 affected members of a small African American kindred. L inkage analysis to genetic markers near autosomal dominant hereditary spastic pa raplegia loci on chromosomes 2p and 14q was performed. The coding sequence of th e SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal contro ls. Results: Every affected individual had signs of uncomplicated spastic parapa resis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis sugg ested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene r evealed a missense mutation C635T, predicted to result in a threonine to isoleuc ine substitution at codon 156. Analysis of 200 normal chromosomes did not identi fy the same change in healthy subjects. Conclusion: We report a novel muta tion in the SPG3A gene in an African American family with an infantile onset of auto somal dominant hereditary spastic paraplegia.
文摘Mutations in the SPG3A gene cause a form of pure, earlyonset autosomal dominant hereditary spastic paraplegia linked to chromosome 14q. The encoded protein, atlastin, is a putative member of the dynamin superfamily of large GTPases involved in cellular trafficking patterns. We report a new atlastin mutation causing spastic paraplegia in association with axonal neuropathy in an Italian family.
基金This study was supported by the grants from the Chinese 863 HiTech Project (No.2001AA221102)the Guangdong Provincial Natural Science Foundation (No.031673)the Guangzhou Municipal Science and Technology Bureau (No. 200223-C7191and No.2004Z3-C7501)
文摘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.
基金supported by the Chinese 863 Hi-Tech Project(Grant No.2001AA221102)the Natural Science Foundation of Guangdong Province(Grant No.031673)the China Medical Board of New York(Grant No.01-759).
文摘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.
基金Supported by National Natural Science Foundation of China,No.81171068
文摘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.
基金This study was supported by the National Scientific Foundations of China(81000484)Natural Scientific Fundation of Zhejiang Province(LY17H090002)+2 种基金the Research Fundation of Zhejiang Health(2008QN017,2016144072)the Natural Science Foundation of Shandong Province(ZR2013HQ016)the Key Research and Development Project of Shandong Province(2015GGH318011).
文摘Background:The hereditary spastic paraplegias(HSPs)are a group of clinically and genetically heterogeneous disorders.Approximately 10% of the autosomal dominant(AD)HSPs(ADHSPs)have the spastic paraplegia 3A(SPG3A)genotype which is caused by ATL1 gene mutations.Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear.The study aims to investigate the genotypephenotype correlation in SPG3A patients.Methods:We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.Results:Most HSPs-SPG3A patients exhibited an early age at onset(AAO)of<10 years old,and showed an autosomal dominant pure spastic paraplegia.We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes,with distal atrophy being the most common complicated symptom.The AAO of each mutation group was not statistically significant(P>0.05).The mutational spectrum associated with ATL1 gene mutation is wide,and most mutations are missense mutations,but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.Conclusions:Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients.We also find that exons 4,7,8 and 12 are mutation hotspots in ATL1 gene.
