Possible anticipation in hereditary spastic paraplegia type 4 ( SPG4 ). (2007 Jun)
possible anticipation in hereditary spastic paraplegia type 4 ( SPG4 ) . objective : We report a multigenerational family with uncomplicated hereditary spastic paraplegia type 4 and apparent anticipation . genetic analysis of the proband revealed a frame shift mutation ( 5 base pair deletion ) in exon 9 of the SPG4 gene encoding the spastin protein . We hypothesized that this deletion mutation may be dynamic and variability in the size of the deletion could account for the anticipation . methods : clinical and genetic analysis of this family and the deletion mutation . results : In this family , the age of onset , which ranges from 3 to 50 years shows an average decrease in the age of onset of 21 . 8 years per transmission over three generations . genetic analysis of multiple family members indicates that all affected members carry the same c . 1340 1344deltataa mutation and that it is not dynamic . conclusion : In this family , other molecular mechanisms may contribute to development of anticipation .

Mutation analysis of the spastin gene ( SPG4 ) in patients with hereditary spastic paraparesis. (2000 Oct)
mutation analysis of the spastin gene ( SPG4 ) in patients with hereditary spastic paraparesis . background : hereditary spastic paraparesis is a genetically heterogeneous condition . recently , mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21 22 . objectives : To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene ( SPG4 ) on chromosome 2p21 22 . methods : DNA from 32 patients ( 12 from families known to be linked to SPG4 ) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing . All patients were also examined clinically . results : thirteen SPG4 mutations were identified , 11 of which are novel . these mutations include missense , nonsense , frameshift , and splice site mutations , the majority of which affect the AAA cassette . We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation . conclusions : recurrent mutations in the spastin gene are uncommon . This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis . Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients .

Spastin gene mutations in bulgarian patients with hereditary spastic paraplegia. (2006 Nov)
spastin gene mutations in bulgarian patients with hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system . The most common genetic form accounting for about 40 of the autosomal dominant HSP ( adhsp ) cases is spastin gene , SPG4 . We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups ( bulgarian , turks and gypsies ) and found four new mutations and one already reported . The phenotype genotype correlations in bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice site mutations . Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation . The clinical and genealogical findings in bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal dominant trait is a strong indication for spastin mutation screening .

Spg3a : An additional family carrying a new atlastin mutation. (2002 Dec)
spg3a : An additional family carrying a new atlastin mutation . The authors report on a novel frameshift mutation ( c . 1688insa ) in the spg3a gene resulting in premature translation termination of the gene product atlastin . these data add a new variant to the second disease gene in autosomal dominant hereditary spastic paraplegia ( adhsp ) and lend definitive support to its causative role . By combining direct testing of spast and spg3a , at least 50 of adhsp families can now receive appropriate genetic diagnosis .

Spg3a mutation screening in english families with early onset autosomal dominant hereditary spastic paraplegia. (2003 Nov)
spg3a mutation screening in english families with early onset autosomal dominant hereditary spastic paraplegia . mutations in the spg3a gene encoding the novel gtpase atlastin have recently been implicated in causing autosomal dominant hereditary spastic paraplegia ( adhsp ) in six unrelated families . The phenotype of affected individuals in all cases has been of an early onset uncomplicated form of the disease . One particular missense mutation , r239c , in exon 7 of spg3a has been identified in three of these families . We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the spg3a gene in affected individuals from 12 unrelated english families , all with an early onset uncomplicated adhsp in whom spastin mutations had previously been excluded . The r239c mutation was found to co segregate with the disease in one english adhsp family confirming a widespread prevalence for this commonly occurring mutation . No additional spg3a mutations were identified in the remaining 11 families suggesting that even within this specific sub set of early onset uncomplicated adhsp patients atlastin mutations are relatively rare .

Missense and splice site mutations in SPG4 suggest loss of function in dominant spastic paraplegia. (2002 May)
missense and splice site mutations in SPG4 suggest loss of function in dominant spastic paraplegia . We studied nine italian families with a pure form of autosomal dominant spastic paraplegia ( adhsp ) to assess the frequency of mutations in the SPG4 gene . We observed marked intrafamilial variability in both age at onset and clinical severity , ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70 . Four of nine probands harboured SPG4 mutations , We identified three new SPG4 mutations , all predicting a loss of func tion with apparently important consequences for spastin function . RT PCR studies predict loss of function as a possible mechanism leading to spastin related HSP . The current study expands the spectrum of allelic variants in SPG4 , confirming their pathological significance in pure AD HSP and suggesting implications for the presumed function of spastin .

SPG4 founder effect in french canadians with hereditary spastic paraplegia. (2007 Jun)
SPG4 founder effect in french canadians with hereditary spastic paraplegia . background : The most common cause of autosomal dominant hereditary spastic paraplegia ( HSP ) is mutations in the SPG4 gene . We have previously identified novel SPG4 mutations in a collection of north american families including the c . g1801a mutation present in two families from quebec . The aim of this study is to estimate the frequency of the c . g1801a mutation in the french canadian ( FC ) population and to determine whether this mutation originates from a common ancestor . methods : We collected and sequenced exon 15 in probands of 37 families . genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families . clinical information was reviewed by a neurologist with expertise in HSP . results : We have identified three additional unrelated families with the c . g1801a mutation and haplotype analysis revealed that all five families share a common ancestor . The mutation is present in 7 of all our FC families and explains half of our spastin linked FC families . The phenotype associated with the c . g1801a genotype is pure HSP with bladder involvement . conclusion : In this study we have determined that the relative frequency of the c . g1801a mutation in our FC collection is 7 , and approximately 50 in the spastin positive FC group . This mutation is the most common HSP mutation identified in this population …

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. (2006 May)
eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs . mutations in the SPG4 gene , which encodes spastin protein , are responsible for up to 45 of autosomal dominant cases . objective : To search for disease causing mutations in a large series of italian patients with HSP . design : samples of DNA were analyzed by direct sequencing of all exons in SPG4 . samples from a subset of patients were also analyzed by direct sequencing of all exons in spg3a , SPG6 , spg10 , and spg13 . setting : molecular testing facility in italy . patients : sixty unrelated italian patients with pure ( n 50 ) and complicated ( n 10 ) HSP . MAIN outcome measures : mutations in SPG4 , spg3a , SPG6 , spg10 , and spg13 . results : We identified 12 different mutations , 8 of which were novel , in 13 patients . No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene . conclusions : The overall rate of mutation in the SPG4 gene within our sample was 22 , rising to 26 when only patients with pure HSP were considered . The negative result obtained in 15 patients without …

Disease related phenotypes in a drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. (2005 Nov)
disease related phenotypes in a drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine . hereditary spastic paraplegias ( HSPs ) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs . dominant mutations in the human SPG4 gene , encoding spastin , are responsible for the most frequent form of HSP . spastin is an atpase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines . furthermore , its drosophila homolog , drosophila spastin ( dspastin ) , has been recently shown to regulate microtubule stability and synaptic function at the drosophila larval neuromuscular junction . Here we report the generation of a spastin linked HSP animal model and show that in drosophila , neural knockdown of dspastin and , conversely , neural overexpression of dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease , including adult onset , locomotor impairment , and neurodegeneration . At the subcellular level , neuronal expression of both dspastin RNA interference and mutant dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse . In addition , we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo . Our findings demonstrate that loss of spastin function elicits HSP like phenotypes in drosophila , provide novel insights into the molecular mechanism of spastin mutations , and raise the possibility that therapy with vinca …

A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin ( SPG4 ) gene … (2001 Nov)
A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin ( SPG4 ) gene : association with multiple sclerosis in two affected siblings and epilepsy in other affected family members . hereditary spastic paraparesis ( HSP ) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness . Some forms have been associated with white matter lesions and complex phenotypes . This study was prompted by the diagnosis of multiple sclerosis ( MS ) in two sisters from a large pedigree with hereditary spastic paraparesis . twelve affected members of the extended family were examined ( MRI and EEG were carried out and evoked potentials measured in five ) , and historical information was obtained from six affected deceased persons . The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons . None of the extended family had evidence of MS . genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delt frameshift mutation in exon 10 . This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations . The possible relevance of the concurrence of HSP and MS in the sib pair is discussed .

Spastin related hereditary spastic paraplegia with dysplastic corpus callosum. (2005 Aug)
spastin related hereditary spastic paraplegia with dysplastic corpus callosum . Thin corpus callosum has been recently observed in two patients with an autosomal dominant trait of hereditary spastic paraplegia ( HSP ) linked to a novel mutation in the spastin gene ( SPG4 ) . In the same two patients cerebellar atrophy has been found . reportedly , in other members of the same family , there has been a variable presence of mental retardation . We report on the clinical and genetic investigation of an austrian family with a novel mutation in the spastin gene . genetic analysis of the SPG4 locus revealed a mutation ( c1120a ) and a known intronic polymorphism ( 996 47G A ) of the spastin gene . In one affected family member , previously undescribed dysplasia of the corpus callosum ( CC ) was found in conjunction with otherwise uncomplicated HSP . dysplastic CC was not paralleled with cortical atrophy , cognitive impairment or other phenotypic variations . Two further affected family members showed the same mutation and polymorphism , but no evidence of CC abnormalities . We conclude that apparently pure HSP may present with MRI features of dysplastic CC . This finding extended the spastin related phenotype which is distinct from previous reports of thin CC in HSP .

Four mutations of the spastin gene in japanese families with spastic paraplegia. (2006 Aug)
Four mutations of the spastin gene in japanese families with spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs . HSP is caused by failure of development or selective degeneration of the corticospinal tracts , which contain the longest axons in humans . The most common form of HSP is caused by mutations of the spastin gene ( spast ) , located on chromosome 2p21 p22 , which encodes spastin , one of the atpases associated with diverse cellular activities ( AAA ) . In this study , we detected four causative mutations of spast among 14 unrelated patients with spastic paraplegia . Two missense mutations ( 1447a G , 1207c G ) and two deletion mutations ( 1465delt , 1475 1476delaa ) were located in the AAA cassette region . three of these four mutations were novel . previous reports and our results suggest that the frequency of spast mutations is higher among japanese patients with autosomal dominant HSP , although spast mutations are also observed in patients with sporadic spastic paraplegia .

Spg20 is mutated in troyer syndrome , an hereditary spastic paraplegia. (2002 Jul)
spg20 is mutated in troyer syndrome , an hereditary spastic paraplegia . troyer syndrome ( TRS ) is an autosomal recessive complicated hereditary spastic paraplegia ( HSP ) that occurs with high frequency in the Old order amish . We report mapping of the TRS locus to chromosome 13q12 . 3 and identify a frameshift mutation in spg20 , encoding spartin . comparative sequence analysis indicates that spartin shares similarity with molecules involved in endosomal trafficking and with spastin , a molecule implicated in microtubule interaction that is commonly mutated in HSP .

The genetics of movement disorders spinocerebellar degenerations background : hereditary movement disorders include spinocerebellar disorders , a large and heterogeneous … (2004 Sep)
The genetics of movement disorders spinocerebellar degenerations background : hereditary movement disorders include spinocerebellar disorders , a large and heterogeneous group of syndromes with ataxia or spasticity as the prominent symptom . In spite of the vast clinical and genetic heterogeneity , patterns of pathogenesis slowly emerge and help us understand these disorders . material AND methods : This review is based on personal experience and recent literature . results : More than 20 types of hereditary spastic paraparesis have been reported . dominant SPG4 and SPG3 with mutations in the spastin or the atlastin gene have been identified in many countries . The most prevalent type of recessive ataxia in europe , friedreich s ataxia , has become a model of integrated clinical molecular therapeutic research . More recessive ataxias ( AOA1 2 ) have been described recently . More than 20 autosomal dominant ataxias have been reported , with 12 identified genes including the episodic ataxias , and 9 mapped . SCA7 appears to be the most frequent type in some nordic countries . interpretation : A striking feature of many of these diseases is the involvement of very different genes for similar phenotypes . conversely , very heterogeneous phenotypes are due to single gene defects . recently there has been considerable progress in the clinical description of movement disorders and the understanding of their genetic basis . possible therapies are emerging .

The role of hereditary spastic paraplegia related genes in multiple sclerosis. (2007 Nov)
The role of hereditary spastic paraplegia related genes in multiple sclerosis . A study of disease susceptibility and clinical outcome . multiple sclerosis ( MS ) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome . It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss . The clinical similarities between hereditary spastic paraplegia ( HSP ) and progressive MS , along with their analogous profiles of axonal loss in the long tracts , make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS . A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity . The MS cases were taken from opposite extremes of the putative distribution of long term outcome using the most stringent clinical criteria to date . genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP ( paraplegin , nipa1 , kif5a , hspd1 , atlastin , spartin , spastin , PLP1 , l1cam , maspardin and bscl2 ) play a role in susceptibility to , or modifying the course of , MS , although small effects of these genes cannot be ruled out .

Phenotype of AD HSP due to mutations in the spast gene : comparison with AD HSP without mutations. (2001 Jan)
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 …

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. (2000 Nov)
novel mutations in spastin gene and absence of correlation with age at onset of symptoms . autosomal dominant hereditary spastic paraplegia is genetically heterogeneous , with at least five loci identified by linkage analysis . recently , mutations in spastin were identified in SPG4 , the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22 . We identified five novel mutations in the spastin gene in five families with SPG4 mutations from north america and tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms .

A de novo spast mutation leading to somatic mosaicism is associated with a later age at onset in HSP. (2007 Jul)
A de novo spast mutation leading to somatic mosaicism is associated with a later age at onset in HSP . SPG4 / spast , the gene encoding spastin , is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia ( HSP ) . SPG4 HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation , especially regarding the severity and the age at onset . In this study , we investigated the origin of the mutation and the factors involved in intra familial heterogeneity in a family with a SPG4 mutation . We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather , who was the only affected member of six siblings . His disease began at age 55 , much later than in his daughter , who had onset at age 18 , and his grandson , in whom onset was at age 5 . these observations indicate that de novo mutations can occur in SPG4 , and that somatic mosaicism might account for intra familial variation in SPG4 linked HSP .

Infantile onset of hereditary spastic paraplegia poorly predicts the genotype. (2007 Jun)
infantile onset of hereditary spastic paraplegia poorly predicts the genotype . Age of symptom onset of hereditary spastic paraplegia varies from infancy to the eighth decade . infantile onset of hereditary spastic paraplegia without a positive family history may cause difficulties in reaching the correct diagnosis and misdiagnosis as a diplegic form of cerebral palsy is particularly common . infantile onset of hereditary spastic paraplegia caused by mutations in the spastin gene ( spast ) is very rare and previously was mostly associated with codominant mutations in this gene . We present a kindred with infantile onset of spastic paraplegia in three successive generations caused by confirmed de novo novel mutation 1537g A ( g471d ) in spast . several family members were previously diagnosed as having cerebral palsy . infantile onset of hereditary spastic paraplegia may be caused by mutations in multiple genes , and this phenotype does not reliably predict the genotype . pediatric neurologists need to be aware of relatively frequent de novo mutations in hereditary spastic paraplegia genes and a possibility that this condition presents in infancy without a positive family history .

Novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia. (2006 Jun)
novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia . spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin ( SPG4 ) , a member of the AAA protein family . A cohort of 34 unrelated italian patients with pure spastic paraplegia , of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic , were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography . We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia . We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene ( one missense mutation , c . 1304 C T ; one nonsense mutation , c . 807C A ; two frameshift mutations , c . 1281dupt , c . 1514 1515insata ; and one splicing mutation , c . 1322 2A C ) . The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44 . 4 . This study contributes to expand the spectrum of SPG4 mutations in italian population .