SPAST Mutations Research Articles

Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia.

Background and PurposeHereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively.MethodsDirect sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes.ResultsTen different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected.ConclusionsWe conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.

Hereditary Spastic Paraplegia with a Novel SPAST Mutation Misdiagnosed with Subacute Combined Degeneration

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is due to mutations in the "spastin" gene (SPAST gene) encoding the AAA protein. The main clinical features of "pure" HSP are progressive lower-limb spasticity with corticospinal tracts and dorsal column degeneration without peripheral neuropathy. Here we report the case of HSP with novel SPAST gene mutation that misdiagnosed with subacute combined degeneration initially. A 58-year-old man with gait disturbance came to our hospital. He was unable to regulate his steps by himself. The impaired gait began 3 years after he had undergone subtotal gastrectomy and chemotherapy for 6 months. Thereafter, he started feeling tingling sensations in the hands and feet and acquired gait difficulties. He denied having a family history of abnormal gait or developmental problem. We diagnosed him with subacute combined degeneration on the evidence of history of gastrectomy, lower normal limit of vitamin B12 (363 pg/ml), apparent absence of vibration sensations and paresthesia in the feet. He was intramuscularly administered cyanocobalamin regularly. However, there was no improvement in his condition. We reconsidered his symptoms and signs, decided to examine the SPAST gene, which is the most common mutation in HSP. The SPAST gene, c.870+1delG, heterozygote, splicing mutation is detected from the gene sample. There was no previous information of this polymorphism or mutation at this locus. We examined his two children, and the same mutation was founded in his son. We report a patient of novel SPAST gene mutation with AD-HSP which is misdiagnosed with SCD.

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

SUMMARYHereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

SPAST mutations in Australian patients with hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is often caused by mutations in the SPAST gene. The frequency of SPAST mutations causing HSP in Australian patients is currently unknown. We aimed to determine the frequency of SPAST gene mutations in our cohort of HSP patients. We recruited 30 unrelated patients with HSP for clinical and genetic assessment. DNA or RNA was extracted from patients' samples to perform direct DNA sequencing of the SPAST gene, multiplex ligation-dependent probe amplification (MLPA) and/or cDNA analysis. We identified 13 heterozygous SPAST mutations in 16 unrelated patients. Most mutations (75%) were detected by DNA sequence analysis. We identified nine-point mutations (n = 9), insertion (n = 1), one type of splice site mutation (n = 2), one type of exonic deletion (n = 2) and one type of exonic amplification (n = 2). Missense mutations (n = 7) were the most frequent mutation type (44%). Heterozygous exonic deletion (n = 2) and heterozygous exonic amplification (n = 2) were identified by MLPA and cDNA screening (25%). We also identified the single heterozygous p.Ser44Leu polymorphism in two other patients without pathogenic mutations in SPAST. We conclude that SPAST mutations are responsible for the majority of HSP in Australia. Most of the patients with SPAST mutations had pure forms of HSP and a positive family history to suggest autosomal dominant (AD) HSP. Not all mutations were identified by direct sequencing of the SPAST gene, necessitating further molecular analysis. Given that SPAST mutations cause AD-HSP, these findings are important when providing genetic counselling for affected patients.

ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes

SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

Novel and recurrent spastin mutations in a large series of SPG4 Italian families

BackgroundHereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders, genetically classified according to the identified disease gene or locus. Clinically, HSP are distinguished in pure and complicated forms. Mutations in the spastin gene (SPAST) are responsible for SPG4 and account approximately for 50% of the dominantly inherited paraplegias with a pure HSP phenotype. MethodsMolecular screening of the SPAST gene allowed the identification of 31 Italian mutation carriers, from 19 unrelated families. Genetic testing was performed by direct sequencing and multiplex ligation-dependent probe amplification. Subjects carrying SPAST mutations were retrospectively evaluated for clinical phenotype and disability score assessment. ResultsWe found 12 recurrent mutations, and 7 novel SPAST mutations. Twenty-eight patients exhibited a pure spastic paraplegia phenotype, while 3 subjects were asymptomatic mutation carriers. Four patients were sporadic cases. Age at onset ranged from 10 to 61 years. Disability score increased with age at examination and disease duration. Patients with onset >38 years presented a faster disease progression, and a higher disability functional index, than the patients with earlier onset (p<0.04). ConclusionsOur study enlarges the number of pathogenic SPAST mutations, and confirms the association with a pure spastic paraplegia phenotype. Age at onset was highly variable and correlates with the rate of disease progression. Future longitudinal clinical studies are needed to confirm these observations.

Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Defects in the SPG4 and SPG3A genes are the two leading causes of HSPs with autosomal dominant inheritance (AD-HSPs). The purpose of this study was to investigate the clinical features and associated genetic mutations in Taiwanese families with AD-HSP. Four kindreds with AD-HSP were recruited, and clinical data were collected from the affected individuals. Genetic studies were conducted in the following order: sequence analysis of the SPG4 gene (SPAST) exons, multiplex ligation-dependent probe amplification to detect genetic rearrangements in SPAST, and sequence analysis of the SPG3A gene exons. Four different SPAST mutations were detected, including a novel small deletion, a missense mutation, and two gross deletions involving exon 17. Although all symptomatic cases manifested as uncomplicated phenotypes, considerable intrakindred and interkindredvariations in terms of age at onset, rate of progression, and severity of disease were observed. Mutation patterns and phenotypic expressivity are heterogeneous in Taiwanese patients with SPG4-related HSP. Genetic rearrangements could be a significant cause of SPG4-related HSP in the Taiwanese population. Assessment of the large deletions that could present in SPAST is warranted when direct sequencing is uninformative.

A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50-60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.

073 Hereditary spastic paraplegia caused by spastin (SPAST, SPG4) mutations is found more often in males: report of novel mutations from one centre, and review of published literature

BackgroundHereditary spastic paraplegia (HSP) is characterised predominantly by slowly progressive spastic paraparesis. Early reports yielded conflicting results concerning sex differences in severity and prevalence of HSP in general. Around 40%...

Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia

PurposeAutosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined. MethodsWe used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia. ResultsWe describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches. ConclusionWe hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients.

Child Neurology: Hereditary spastic paraplegia in children

Because the medical literature on hereditary spastic paraplegia (HSP) is dominated by descriptions of adult case series, there is less emphasis on the genetic evaluation in suspected pediatric cases of HSP. The differential diagnosis of progressive spastic paraplegia strongly depends on the age at onset, as well as the accompanying clinical features, possible abnormalities on MRI, and family history. In order to develop a rational diagnostic strategy for pediatric HSP cases, we performed a literature search focusing on presenting signs and symptoms, age at onset, and genotype. We present a case of a young boy with a REEP1 (SPG31) mutation. A 4-year-old boy presented with progressive walking difficulties from the time he started walking at the age of 12 to 13 months. His family history was significant for minimal gait abnormalities with onset after age 35, occurring in the patient's mother, maternal grandfather, and maternal aunt; none of them had ever sought medical attention. Neurologic examination revealed a mildly spastic gait and marked lower limb hyperreflexia with bilateral Babinski signs present. Vibration perception was reduced at the ankles. Neurologic examination of the patient's mother and maternal aunt revealed subtle gait abnormalities with bilateral Babinski signs present. MRI of the brain and spinal cord and general metabolic screening revealed no abnormalities. Diagnostic genetic testing in both the patient and his mother revealed a pathogenic mutation (c.417 + 1 G>T) in REEP1 (SPG31) which causes a pure HSP. Mutations in ATL1 (SPG3A) and SPAST (SPG4) had previously been excluded. HSP is a genetically and clinically heterogeneous group of disorders in which the main clinical feature is progressive lower limb spasticity secondary to pyramidal tract dysfunction. HSP is classified as pure if neurologic signs are limited to the lower limbs (although urinary urgency and mild impairment of vibration perception in the distal lower …

TRANSLATIONAL IMPACT

The hereditary spastic paraplegias (HSP) are a collection of neurodegenerative disorders characterised by progressive weakness and spasticity of the legs. They are caused by developmental failure or degeneration of motor axons, or nerve fibres, in the corticospinal tract, and are an important cause of permanent disability. Around 40% of autosomal dominant cases of HSP are caused by mutations in the SPAST gene. HSP cases show highly variable age of onset and severity, both between and within families, and haploinsufficiency for SPAST is the likely mechanism in most cases.Current treatments to provide symptomatic relief for HSP include muscle relaxants to relieve spasticity, and physical therapy to maintain muscle strength and range of movement. However, these treatments do not alter or slow the disease, and the development of effective therapies has been hampered by a lack of knowledge regarding the molecular mechanisms underlying axonal degeneration.Previous work has shown that spastin, the SPAST gene product, shares homology with the p60 subunit of katanin, and both proteins have been shown to be ATP-dependent microtubule-severing proteins. Microtubules, components of the cell’s cytoskeleton, are fundamentally important for the correct outgrowth of axons, but how microtubule-severing activities might relate to axonal degeneration in HSP is unclear. This study uses confocal time-lapse imaging in the zebrafish embryonic CNS to demonstrate that both spastin and katanin are required in axons for the formation of forward-moving dynamic microtubules, and also at the growth cone, the specialised guidance structure at the axon’s growing tip. The effects of lowering the levels of spastin and katanin, mimicking haploinsufficiency, were monitored in embryonic neurons using a fluorescent protein as a marker for the growing microtubules. Reduced expression of either spastin or katanin severely impaired formation of dynamic microtubules and inhibited outgrowth of axons and growth cone motility. The microtubule-destabilising drug nocodazole also abolished microtubule dynamics, suppressed growth cone motility and enhanced the severity of the phenotypes caused by reduced spastin expression in the embryos.These results reveal crucial functions for microtubule-severing proteins in neuronal development, through their roles in dynamic microtubule formation, axonal outgrowth and growth cone protrusive activity. SPAST mutations might cause depletion of the pool of dynamic microtubules in neurons, leading to a failure to maintain long axons and the axonal transport machinery within, which could explain the distal axonopathies that are observed in HSP patients. Future studies will aim to identify compounds that modulate microtubule dynamics, which might be of therapeutic value for treatment of HSP.

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

BackgroundHereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases.MethodsWe defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).ResultsWe found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.ConclusionsIn a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.

Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations

BackgroundIn the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form.ObjectiveTo provide...

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutation-negative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by multiplex ligation-dependent probe amplification assay. We could not identify potentially disease-causing mutations in our patients either by mutation scanning or by gene dosage analysis, as for the latter specific positive controls are not available to date. As our sample represents ADHSP patients for whom SPAST mutations and almost in all cases ATL1 and REEP1 mutations had been excluded, we consider SLC33A1 gene mutations as being very rare in a European ADHSP cohort, if present at all. To date, as SPG42 has still not been identified in a second, unrelated family, systematic genetic testing for SLC33A1 mutations is not recommended.

Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST gene

Bovine spinal dysmyelination (BSD) is a recessive congenital neurodegenerative disease in cattle (Bos taurus) characterized by pathological changes of the myelin sheaths in the spinal cord. The occurrence of BSD is a longstanding problem in the American Brown Swiss (ABS) breed and in several European cattle breeds upgraded with ABS. Here, we show that the disease locus on bovine chromosome 11 harbors the SPAST gene that, when mutated, is responsible for the human disorder hereditary spastic paraplegia (HSP). Initially, SPAST encoding Spastin was considered a less likely candidate gene for BSD since the modes of inheritance as well as the time of onset and severity of symptoms differ widely between HSP and BSD. However, sequence analysis of the bovine SPAST gene in affected animals identified a R560Q substitution at a position in the ATPase domain of the Spastin protein that is invariant from insects to mammals. Interestingly, three different mutations in human SPAST gene at the equivalent position are known to cause HSP. To explore this observation further, we genotyped more than 3,100 animals of various cattle breeds and found that the glutamine allele exclusively occurred in breeds upgraded with ABS. Furthermore, all confirmed BSD carriers were heterozygous, while all affected calves were homozygous for the glutamine allele consistent with recessive transmission of the underlying mutation and complete penetrance in the homozygous state. Subsequent analysis of recombinant Spastin in vitro showed that the R560Q substitution severely impaired the ATPase activity, demonstrating a causal relationship between the SPAST mutation and BSD.

Erratum: Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia

Correction to: European Journal of Human Genetics (2009) 17, 187–194; doi:10.1038/ejhg.2008.147; published online 13 August 2008 Since the publication of the above paper, the authors have identified major errors in Table 1. The amended table is reproduced below. The authors would like to apologise for this mistake.

Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia

The SPAST gene encoding for spastin plays a central role in the genetically heterogeneous group of diseases termed hereditary spastic paraplegia (HSP). In this study, we attempted to expand and refine the genetic and phenotypic characteristics of SPAST associated HSP by examining a large cohort of HSP patients/families. Screening of 200 unrelated HSP cases for mutations in the SPAST gene led to detection of 57 mutations (28.5%), of which 47 were distinct and 29 were novel mutations. The distribution analysis of known SPAST mutations over the structural domains of spastin led to the identification of several regions where the mutations were clustered. Mainly, the clustering was observed in the AAA (ATPases associated with diverse cellular activities) domain; however, significant clustering was also observed in the MIT (microtubule interacting and trafficking), MTBD (microtubule-binding domain) and an N-terminal region (228-269 residues). Furthermore, we used a previously generated structural model of spastin as a framework to classify the missense mutations in the AAA domain from the HSP patients into different structural/functional groups. Our data also suggest a tentative genotype-phenotype correlation and indicate that the missense mutations could cause an earlier onset of the disease.

G.P.18.10 A novel duplication in the SPAST gene associated to gender difference of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a heterogeneous condition associated to progressive weakness and spasticity of the lower limbs. The most frequent form is the autosomal dominant (AD) SPG4 form caused by mutations in the SPAST gene at the SPG4 locus (Fink 2006) and characterized by large inter- and intrafamilial variability in age at onset and disease severity. The broad spectrum of SPAST mutations has recently been further extended by the finding of large genomic deletions in SPG4-linked pedigrees, which had screened negative for “small” mutations.