The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia.
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ABSTRACT:
SUBMITTER: Guthrie G
PROVIDER: S-EPMC3590400 | biostudies-literature | 2013 Mar
REPOSITORIES: biostudies-literature
Publications
The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia.
Guthrie Grant G Pfeffer Gerald G Bailie Maura M Bradshaw Karen K Browning Andrew C AC Horvath Rita R Chinnery Patrick F PF Yu-Wai-Man Patrick P
Journal of neurology 20121213 3
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Project description:BackgroundPoint mutations in SPG4, the gene encoding spastin, are a frequent cause of autosomal dominant hereditary spastic paraplegia (AD-HSP). However, standard methods for genetic analyses fail to detect exonic microdeletions.Methods121 mutation-negative probands were screened for rearrangements in SPG4 by multiplex ligation-dependent probe amplification.Results24 patients with 16 different heterozygotic exon deletions in SPG4 (20%) were identified, ranging from one exon to the whole coding sequence. Comparison with 78 patients with point mutations showed a similar clinical picture but an earlier age at onset.ConclusionsExon deletions in SPG4 are as frequent as point mutations, and SPG4 is responsible for 40% of AD-HSP.
| S-EPMC2598038 | biostudies-literature
Project description:The spectrum of mutations (missense, non-sense and splice-site) associated with hereditary spastic paraplegia 4 (HSP-SPG4) (SPG4:OMIM#182601) has suggested that this autosomal dominant disease results from loss of function. Because the protein encoded by SPG4, termed spastin, is a microtubule-severing enzyme, a loss-of-function scenario for the disease suggests that corticospinal axons degenerate due to inadequate microtubule severing resulting from inactivation of one spastin allele. Lending more complexity to the situation, there are two major isoforms of spastin (M1 and M87) translated from two start codons. M87 is widely expressed, while M1 is appreciably detected only in adult spinal cord. Here, we focused on four HSP-associated mutations of the SPG4 gene located outside of the AAA region essential for microtubule severing. We found that none of these mutations affected the enzymatic activity or expression levels of either M1 or M87. Three of the mutations resulted in dominant-negative activity of M1. Surprisingly, the S44L mutation, which is asymptomatic when present heterozygously, conferred dominant-negative activity, while the E112K mutation, which is symptomatic when present heterozygously, did not. Clinical symptoms reported for patients carrying the dominant-negative mutations L195V or 46Stop are not more severe than those reported for patients carrying the non-dominant-negative E112K mutation. These results indicate that there are cases of HSP-SPG4 that cannot be explained by insufficient spastin microtubule-severing activity.
| S-EPMC2893808 | biostudies-literature
Project description:Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders, it share common symptom - of progressive lower spastic paraparesis. The most common autosomal dominant (AD) forms of HSP are SPG4 (SPAST gene) and SPG3 (ATL1 gene). In the current research we investigated for the first time the distribution of pathogenic mutations in SPAST and ATL1 genes within a large cohort of Russian HSP patients (122 probands; 69 famillial cases). We determined the frequencies of genetic abnormalities using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and Next Generation Sequencing (NGS) of targeted gene panels. As a result, SPG4 was diagnosed in 30.3% (37/122) of HSP cases, where the familial cases represented 37.7% (26/69) of SPG4. In total 31 pathogenic and likely pathogenic variants were detected in SPAST, with 14 new mutations. Among all detected SPAST variants, 29% were gross deletions and duplications. The proportion of SPG3 variants in Russian cohort was 8.2% (10/122) that were all familial cases. All 10 detected ATL1 mutations were missense substitutions, most of which were in the mutational hot spots of 4, 7, 8, 12 exons, with 2 novel mutations. This work will be helpful for the populational genetics of HSP understanding.
| S-EPMC6783457 | biostudies-literature
Project description:BACKGROUND:Hereditary 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. METHODS:We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS:We 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. CONCLUSIONS:In 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.
| S-EPMC2964648 | biostudies-literature
Project description:BackgroundHereditary spastic paraplegia (HSP) is a group of neurogenetic diseases of the corticospinal tract, accompanied by distinct spasticity and weakness of the lower extremities. Mutations in the spastic paraplegia type 4 (SPG4) gene, encoding the spastin protein, are the major cause of the disease. This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.Case summaryA 44-year-old male was admitted to our hospital for long-term right lower limb weakness, leg stiffness, and unstable walking. His symptoms gradually worsened, while no obvious muscle atrophy in the lower limbs was found. Neurological examinations revealed that the muscle strength of the lower limbs was normal, and knee reflex hyperreflexia and bilateral positive Babinski signs were detected. Members of his family also had the same symptoms. Using mutation analysis, a novel heterozygous duplication mutation, c.1053dupA, p. (Gln352Thrfs*15), was identified in the SPG4 gene in this family.ConclusionA Chinese family with HSP had a novel mutation of the SPG4 gene, which is autosomal dominant and inherited as pure HSP. The age of onset, sex distribution, and clinical manifestations of all existing living patients in this family were analyzed. The findings may extend the current knowledge on the existing mutations in the SPG4 gene.
| S-EPMC10237142 | biostudies-literature
Project description: Not available
| S-EPMC7840324 | biostudies-literature
Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA
| PRJNA313999 | ENA
Project description:Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11-/- mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
| S-EPMC10837238 | biostudies-literature
Project description:The goal of this project is to study differentially expressed genes in patients affected by Hereditary Spastic Paraplegia (HSP) linked to mutations of the gene encoding spastin an ubiquitously expressed protein that has recently been shown to be involved in microtubule regulation and vesicle trafficking by cell culture studies. Gene profiling was done with Affymetrix U95Av2 GeneChips using the total RNA extracted from muscle biopsies of 3 SPG4-linked HSP patients.
2007-07-29 | E-GEOD-1300 | biostudies-arrayexpress
Project description:BackgroundHereditary spastic paraplegias (HSPs) are progressively debilitating neurodegenerative disorders that follow heterogenous patterns of Mendelian inheritance. Available epidemiological evidence provides limited incidence and prevalence data, especially at the genetic subtype level, preventing a realistic estimation of the true social burden of the disease. The objectives of this study were to (1) review the literature on epidemiology of HSPs; and (2) develop an epidemiological model of the prevalence of HSP, focusing on four common HSP genetic subtypes at the country and region-level.MethodsA model was constructed estimating the incidence at birth, survival, and prevalence of four genetic subtypes of HSP based on the most appropriate published literature. The key model parameters were assessed by HSP clinical experts, who provided feedback on the validity of assumptions. A model was then finalized and validated through comparison of outputs against available evidence. The global, regional, and national prevalence and patient pool were calculated per geographic region and per genetic subtype.ResultsThe HSP global prevalence was estimated to be 3.6 per 100,000 for all HSP forms, whilst the estimated global prevalence per genetic subtype was 0.90 (SPG4), 0.22 (SPG7), 0.34 (SPG11), and 0.13 (SPG15), respectively. This equates to an estimated 3365 (SPG4) and 872 (SPG11) symptomatic patients, respectively, in the USA.ConclusionsThis is the first epidemiological model of HSP prevalence at the genetic subtype-level reported at multiple geographic levels. This study offers additional data to better capture the burden of illness due to mutations in common genes causing HSP, that can inform public health policy and healthcare service planning, especially in regions with higher estimated prevalence of HSP.
| S-EPMC8944001 | biostudies-literature