Hereditary spastic paraplegia. (2002 Nov)
hereditary spastic paraplegia . The hereditary spastic paraplegias are a large group of clinically similar disorders . seventeen different HSP loci have been discovered thus far . different genetic forms of uncomplicated HSP are clinically very similar . except for the average age at which symptoms appear , different genetic types of uncomplicated HSP cannot be distinguished reliably by clinical parameters alone . For most subjects , HSP is a diagnosis of exclusion . The differential diagnosis includes treatable disorders as well as those for which the prognosis is quite different from HSP . Even with the emerging availability of laboratory testing for HSP gene mutations , it is still essential that alternative disorders be excluded by careful history , examination , laboratory studies , neuroimaging , and neurophysiologic evaluation . uncomplicated HSP is due to axonal degeneration at the ends of the longest motor ( corticospinal tract ) and sensory ( dorsal column fibers ) in the spinal cord . The observation that some forms begin in childhood and are essentially nonprogressive while other forms begin in adulthood and are slowly progressive raises the possibility that some forms of HSP ( e . g . ; those associated with licam gene mutations and possibly those due to spg3a mutations ) are neurodevelopmental disorders ; and other forms are truly neurodegenerative disorders . The mechanisms by which spastin , atlastin , and paraplegin mutations cause axonal degeneration that results in clinically similar forms of HSP are not known . nonetheless …

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 .

Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature. (2006 Sep)
Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature . We report the clinical , structural , functional and genetic characterization of a 37 year old caucasian female , presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum ( CC ) , cognitive impairment , amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC . magnetic resonance imaging ( MRI ) examination revealed a thin CC with fronto parietal cortical atrophy . 18fluordesoxyglucose positron emission tomography ( FDG PET ) showed reduced cortical and thalamic metabolism . By transcranial magnetic stimulation , we delineated a severe impairment of transcallosal inhibition . sequence analysis did not reveal disease causing mutations in the genes slc12a6 ( andermann ) , spastin ( SPG 4 ) , bscl2 ( SPG 17 ) and spartin ( SPG 20 ) . We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described ( 35 with linkage to chromosome 15q13 15 ) . Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons .

Motor system abnormalities in hereditary spastic paraparesis type 4 ( SPG4 ) depend on the type of mutation in the … (2003 Jul)
motor system abnormalities in hereditary spastic paraparesis type 4 ( SPG4 ) depend on the type of mutation in the spastin gene . background : hereditary spastic paraparesis ( HSP ) denotes a group of inherited neurological disorders with progressive lower limb spasticity as their clinical hallmark ; a large proportion of autosomal dominant HSP belongs to HSP type 4 , which has been linked to the SPG4 locus on chromosome 2 . A variety of mutations have been identified within the SPG4 gene product , spastin . objective : correlation of genotype and electrophysiological phenotype . material : Two large families with HSP linked to the SPG4 locus with a very similar disease with respect to age of onset , progression , and severity of symptoms . methods : mutation analysis was performed by PCR from genomic DNA and cDNA , and direct sequencing . The motor system was evaluated using transcranial magnetic stimulation . results : patients differ in several categories depending on the type of mutation present . conclusions : For the first time in hereditary spastic paraparesis , a phenotypic correlate of a given genetic change in the spastin gene has been shown .

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 .

Mutation analysis of SPG4 and spg3a genes and its implication in molecular diagnosis of korean patients with hereditary spastic paraplegia. (2005 Jul)
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 …

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 …

Autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation. (2007 Aug)
autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation . We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia ( adhsp ) . On the basis of maximum LOD score of 1 . 94 at theta ( max ) 0 with marker d2s367 , we obtained suggestive evidence for linkage of adhsp to SPG4 locus . denaturing high performance liquid chromatography ( dhplc ) and direct sequence analysis allowed us to identify a nonsense mutation ( 1741 C T ) in exon 17 of the spastin gene . This transition , carried by all the affected family members and two apparently healthy individuals , lead to truncation of the last 36 amino acids in the C terminus of the protein . these results confirm the existence of mutation in the SPG4 gene with a reduced penetrance , indicating that other genetic or environmental factors are required to trigger full blown disease .

Recent advances in hereditary spastic paraplegia. (2001 Jul)
recent advances in hereditary spastic paraplegia . The hereditary spastic paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity . there has been an exponential increase in the number of HSP loci mapped in recent years , with nine out of the 17 loci reported during the past 2 years . eight loci have now been identified for the autosomal dominant form , and seven of these are associated with pure HSP . spastic paraplegia 4 remains the most frequent locus , and is usually associated with a pure phenotype . although the corresponding spastin gene was only recently identified , over 50 mutations have been described to date , which renders molecular diagnosis difficult . Five loci are known for autosomal recessive HSP , and four of these are associated with complex forms , all with different phenotypes . Two genes have been identified : paraplegin and sacsin . finally , three loci have been identified in X linked HSP , two of which are complex forms . The genes that encode L1 and PLP were the first to be identified in HSP disorders . surprisingly , the five genes encode proteins of different families , making understanding and diagnosis of HSP even more difficult . The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders .

Hereditary spastic paraplegia caused by mutations in the SPG4 gene. (2001 Jan)
hereditary spastic paraplegia caused by mutations in the SPG4 gene . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs . The SPG4 locus at 2p21 p22 accounts for 40 50 of all AD HSP families . The SPG4 gene was recently identified . It is ubiquitously expressed in adult and foetal tissues and encodes spastin , an atpase of the AAA family . We have now identified four novel SPG4 mutations in german AD HSP families , including one large family for which anticipation had been proposed . mutations include one frame shift and one missense mutation , both affecting the walker motif B . Two further mutations affect two donor splice sites in introns 12 and 16 , respectively . RT PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA . All mutations are predicted to cause loss of functional protein . In conclusion , we confirm in german families that SPG4 mutations cause AD HSP . Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency . If a threshold level of spastin were critical for axonal preservation , such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4 linked AD HSP .

Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. (2008 Jan)
structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin . spastin , the most common locus for mutations in hereditary spastic paraplegias , and katanin are related microtubule severing AAA atpases involved in constructing neuronal and non centrosomal microtubule arrays and in segregating chromosomes . The mechanism by which spastin and katanin break and destabilize microtubules is unknown , in part owing to the lack of structural information on these enzymes . Here we report the X ray crystal structure of the drosophila spastin AAA domain and provide a model for the active spastin hexamer generated using small angle X ray scattering combined with atomic docking . The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule . helices unique to the microtubule severing AAA atpases surround the entrances to the pore on either side of the ring , and three highly conserved loops line the pore lumen . mutagenesis reveals essential roles for these structural elements in the severing reaction . peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy terminal tail of tubulin . collectively , our data support a model in which spastin pulls the C terminus of tubulin through its central pore , generating a mechanical force that destabilizes tubulin tubulin interactions within the microtubule lattice . Our work also provides insights into the structural defects in spastin that arise from mutations …

All neuropathies great and small. (2005 Nov)
All neuropathies great and small . autosomal dominant pure hereditary spastic paraplegia ( AD HSP ) is characterized by the degeneration of long axons in corticospinal tracts and dorsal columns , resulting in spasticity and difficulty walking . mutations in the SPG4 gene product spastin are the predominant genetic lesions associated with this inherited disease . In this issue , Orso et al . examine and reconcile existing drosophila mutants of spastin and generate a new model for HSP by overexpression of a fly spastin transgene that carries a mutation prevalent in human AD HSP ( see the related article beginning on page 3026 ) . expression of this mutant spastin protein produces pathology in flies reminiscent of the human disease , including adult locomotion defects , in addition to causing aberrant synaptic morphology and altered microtubule stability . Both movement and synaptic defects in fly mutants were ameliorated by treatment with the microtubule modifying agent vinblastine . The results are consistent with disease causing mutations in human spastin producing dominant negative proteins and confirm the usefulness of drosophila genetic techniques to understand HSP and other neurodegenerative diseases .

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 …

Spastin , the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein. (2006 May)
spastin , the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein . spastin , an atpase belonging to the AAA family of proteins is most commonly mutated in autosomal dominant hereditary spastic paraplegias ( HSP ) . spastin is a multifaceted protein with versatile role in cellular events , principally involved in microtubule dynamics . To gain further insight into the molecular function of spastin , we used the yeast two hybrid approach to identify novel interacting partners of spastin . using spastin as bait , we identified reticulon 1 ( RTN1 ) and reticulon 3 ( RTN3 ) as potential spastin interacting proteins . RTN1 and RTN3 belong to the reticulon ( RTN ) gene family , which are primarily expressed in the endoplasmic reticulum . moreover , RTN1 is known to play a role in vesicular transport processes . using in vitro and in vivo immunoprecipitation experiments , we were able to demonstrate that RTN1 interacts specifically with spastin . intracellular distribution studies using immunostaining and overexpression of epitope tagged protein revealed an obvious colocalization of spastin and RTN1 in discrete vesicles in the cytoplasm . spastin mediates its interaction with RTN1 through its N terminal region containing a microtubule interacting and trafficking domain . It is interesting to note that the aberrant intracellular distribution of a truncated spastin protein was rescued by coexpression with RTN1 , which highlights the physiological significance of this interaction . Our findings strengthen the …

Characterization of a novel spg3a deletion in a french canadian family. (2007 Jul)
characterization of a novel spg3a deletion in a french canadian family . hereditary spastic paraplegias ( HSPs ) are characterized by progressive lower limb spasticity and weakness . mutations in the spg3a gene , which encodes the large guanosine triphosphatase atlastin , are the second most common cause of autosomal dominant hereditary spastic paraplegia . In a large spg3a screen of 70 hereditary spastic paraplegia subjects , a novel in frame deletion , p . del436n , was identified . characterization of this deletion showed that it affects neither the guanosine triphosphatase activity of atlastin nor interactions between atlastin and spastin . interestingly , immunoblot analysis of lymphoblasts from affected patients demonstrated a significant reduction in atlastin protein levels , supporting a loss of function disease mechanism .

Mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia. (2002 Jul)
mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegias ( HSP ) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and hyperreflexia of the lower limbs . autosomal dominant hereditary spastic paraplegia 4 linked to chromosome 2p ( SPG4 ) is the most common form of autosomal dominant hereditary spastic paraplegia . It is caused by mutations in the SPG4 gene encoding spastin , a member of the AAA protein family of atpases . In this study the spastin gene of HSP patients from 161 apparently unrelated families in germany was analyzed . The authors identified mutations in 27 out of the 161 HSP families ; 23 of these mutations have not been described before and only one mutation was found in two families . among the detected mutations are 14 frameshift , four nonsense , and four missense mutations , one large deletion spanning several exons , as well as four mutations that affect splicing . Most of the novel mutations are located in the conserved AAA cassette encoding region of the spastin gene . The relative frequency of spastin gene mutations in an unselected group of german HSP patients is approximately 17 . frameshift mutations account for the majority of SPG4 mutations in this population . The proportion of splice mutations is considerably lower than reported elsewhere .

Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. (2005 Oct)
spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity . HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending ( pyramidal ) and ascending ( dorsal columns ) tracts . In this study , we compared spinal cord magnetic resonance imaging ( MRI ) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia ( spg3a , SPG4 , SPG6 , and SPG8 ) with age matched control subjects . The cross section area of HSP subjects at cervical level C2 was 59 . 42 / 12 . 57 mm2 and at thoracic level T9 was 28 . 58 / 5 . 25 mm2 . Both of these values were less than in the healthy controls ( p 0 . 001 ) . The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy ( 47 . 60 / 6 . 58 mm2 at C2 , 21 . 40 / 2 . 4 mm2 at T9 ) than in subjects with SPG3 and SPG4 ( 66 . 0 / 8 . 94 mm2 at C2 , p 0 . 02 ; 31 . 75 / 2 . 76 mm2 at T9 , p 0 . 001 ) . these observations indicate that spinal …

Spastin gene mutation in chinese patients with hereditary spastic paraplegia objective : To investigate the mutation characteristics of spastin gene … (2003 Jun)
spastin gene mutation in chinese patients with hereditary spastic paraplegia objective : To investigate the mutation characteristics of spastin gene in chinese patients with hereditary spastic paraplegia ( HSP ) and thus provide a basis for the gene diagnosis of HSP . methods : mutation of spastin gene was screened by polymerase chain reaction single strand conformation polymorphism ( PCR SSCP ) combined with DNA direct sequencing in 31 unrelated affected HSP individuals in china , of whom 22 were from autosomal dominant families and 9 were sporadic HSP patients . Co segregation analysis was carried out after the finding of abnormal SSCP bands . results : Six cases were found to have abnormal SCP bands , and among them , two missense mutations ( t1258a , a1293g in exon 8 ) and one deletion mutation ( 1667delact or 1668delcta or 1669deltac in exon 14 ) were found and all of them were not reported previously . They were all co segregated with the disease and were localized within the functional domain of spastin gene . besides , t1258a was seen in two unrelated families . conclusion : The mutation rate ( 18 . 2 ) in autosomal dominant HSP in chinese patients is comparatively low . point mutation is the major mutation type and exon 8 may be the mutation hot spot .

Large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. (2005 Feb)
large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) due to mutations in the spastin gene ( SPG4 ) located to 2p22 p21 is the most common form of autosomal dominant ( AD ) HSP . We performed PCR based direct sequencing of SPG4 , followed by a linkage analysis and subsequent southern blot analysis in large japanese kindred where 20 of 33 members were evaluated neurologically , and consequently 6 were affected with HSP . clinical evaluation showed that the mean age at disease onset of the patients was older and the disability was less severe than those of previously reported typical patients with SPG4 mutations . direct sequencing of genomic DNA and RT PCR product did not show a SPG4 mutation despite of a strong linkage to the SPG4 locus at 2p . southern blot analysis suggested a deletion involving the 5 UTR of SPG4 . further sequence analysis confirmed a heterozygous 2307 bp deletion spanning from the 5 UTR to intron 1 of SPG4 . The results suggested that transcription of the mutated allele starts from an authentic initiation site , but lacks an authentic translational start site of exon 1 because of a deficient splice donor site and coding region . The abnormal transcripts may result in rapid RNA decay . The novel refractory mutation we identified widens the spectrum of SPG4 mutations . these findings suggest that structural …

Identification of nuclear localisation sequences in spastin ( SPG4 ) using a novel tetra GFP reporter system. (2004 May)
identification of nuclear localisation sequences in spastin ( SPG4 ) using a novel tetra GFP reporter system . mutations in the human spastin gene ( SPG4 ) cause the most prevalent form of autosomal dominant hereditary spastic paraplegia ( HSP ) , a neurodegenerative disorder characterised by progressive weakness and spasticity of the lower limbs . We address the question of intracellular localisation of spastin . using polyclonal antibodies against N terminal spastin sequences , we find that the native protein is localised in both the perinuclear cytoplasm and the nucleus . To identify structural motifs within the protein that can explain entry into the nucleus , we developed a reporter system to test nuclear localisation sequence ( NLS ) functionality based on four in frame fused copies of green fluorescent protein . using this novel tool we demonstrate that spastin carries two NLSs located in exons 1 and 6 . Both are independently functional in mediating nuclear entry .