First patient with hereditary spastic paraplegia type 8 in Poland.
Ontology highlight
ABSTRACT:
SUBMITTER: Bogucki P
PROVIDER: S-EPMC5582219 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
First patient with hereditary spastic paraplegia type 8 in Poland.
Bogucki Piotr P Sobczyńska-Tomaszewska Agnieszka A
Clinical case reports 20170725 9
SPG 8 is an autosomal dominant HSP, which phenotype results from KIAA0196 gene mutations. There have been twelve types of KIAA0196 mutations described in HGMD, which are located in conservative region of gene encoding strumpellin. We describe first patient in Poland, simultaneously second in the world with KIAA0196 mutation - p.V620A. ...[more]
Similar Datasets
Project description:Hereditary Spastic Paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPG4 are a major cause of autosomal-dominant HSP. Spastin, the protein encoded by SPG4, is a microtubule-severing protein and is enriched in the distal axon of corticospinal motor neurons which degenerate in HSP patients. How SPG4 mutations cause axon degeneration in patients is not understood. Multipotent neural stem cells, accessible from patient olfactory mucosa biopsies, provided a new patient-derived cell models for HSP. Olfactory neurosphere-derived cells were obtained from cohorts of HSP patients with, and without, mutations in SPG4 and from healthy controls. Patient cells had extensive changes in expression of cell cycle-related genes and in genes associated with microtubule formation. Despite this, cell proliferation and metabolic functions of the patient cells were similar to controls. Cells with mutated SPG4 had significantly less spastin and acetylated tubulin but significantly more stathmin, a tubulin-depolymerising protein. These cells also significant deficits in the intracellular distribution of peroxisomes and mitochondria, compared to control cells. This model reveals that SPG4-HSP patient-derived neural stem/progenitors compensate for the cell cycle-related effects of reduced spastin levels in the nucleus, in part by large changes in gene expression, but failed to correct deficits in organelle trafficking. The results raise the question of whether these deficits arise directly from the loss of spastin or indirectly from the compensation. Patient-derived olfactory stem cells provide a new model for examining the neural consequences of human genetic mutations in their natural setting: at normal gene dosages against normal genetic backgrounds.
2012-12-20 | E-TABM-1180 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6336413 | biostudies-literature
Project description:GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA
| PRJNA313999 | ENA
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:Variants in FA2H have been associated with a wide range of phenotypes including hereditary spastic paraplegia type 35 (SPG35); however, genetically confirmed cases have not been reported in Africa. We report here the first African family with a variant in the FA2H gene causing SPG35. Four affected siblings with consanguineous parents presented with walking difficulty at age 2-3 and progressive limb weakness. They became wheelchair-bound 2 years after disease onset. Neurological examination confirmed lower greater than upper limb weakness and atrophy, brisk reflexes throughout, and spasticity with scissor legs. The patients also had choking, urinary urgency, and mental retardation. A brain MRI showed thin corpus callosum and periventricular leucodystrophy. Testing of 58 SPG genes showed a homozygous variant in FA2H at the exon 5 donor site c.786+1G>A, which has previously been shown to cause skipping of exons 5 and 6 of the gene transcript. This variant segregated with the disease in the family. This variant has been reported previously with a similar phenotype and slow progression in a population with different background. Here, we confirm its pathogenicity and expand its genetic epidemiology. Studying diverse populations may help to increase understanding of the disease mechanism and ultimately lead to therapeutic targets.
| S-EPMC6557683 | biostudies-literature
Project description:Although SPG11 is the most common complicated hereditary spastic paraplegia, our knowledge of the long-term prognosis and life expectancy is limited. We therefore studied the disease course of all patients with a proven SPG11 mutation as tested in our laboratory, the single Dutch laboratory providing SPG11 mutation analysis, between 1 January 2009 and 1 January 2011. We identified nine different SPG11 mutations, four of which are novel, in nine index patients. Eighteen SPG11 patients from these nine families were studied by means of a retrospective chart analysis and additional interview/examination. Ages at onset were between 4 months and 14 years; 39% started with learning difficulties rather than gait impairment. Brain magnetic resonance imaging showed a thin corpus callosum and typical periventricular white matter changes in the frontal horn region (known as the 'ears-of the lynx'-sign) in all. Most patients became wheelchair bound after a disease duration of 1 to 2 decades. End-stage disease consisted of loss of spontaneous speech, severe dysphagia, spastic tetraplegia with peripheral nerve involvement and contractures. Several patients died of complications between ages 30 and 48 years, 3-4 decades after onset of gait impairment. Other relevant features during the disease were urinary and fecal incontinence, obesity and psychosis. Our study of 18 Dutch SPG11-patients shows the potential serious long-term consequences of SPG11 including a possibly restricted life span.
| S-EPMC3798836 | biostudies-literature
Project description:ObjectivesTo investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan.MethodsMutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single-nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation.ResultsNineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito-parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect.InterpretationThis study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent.
| S-EPMC7187706 | biostudies-literature
Project description:Anecdotal oculomotor disturbances have been described in spastic paraplegia type 7 (SPG7). We investigated oculomotor and vestibular dysfunction in five patients with genetically verified SPG7. All five patients exhibited significantly slower velocities of vertical saccades compared to controls, but significantly faster than in progressive supranuclear palsy, with upward saccades being particularly affected. Horizontal saccades, cerebellar oculomotor markers, and vestibuloocular reflex seem to be variably affected. Thus, albeit subclinical in some cases, slowing of the vertical saccades may belong to the phenotype of SPG7 and may serve as a valuable biomarker for differentiation from spastic ataxias and atypical parkinsonism.
| S-EPMC6801205 | biostudies-literature
Project description:We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.
| S-EPMC3819934 | biostudies-literature
Project description:Hereditary spastic paraplegia type 5 is a neurodegenerative disease caused by loss-of-function mutations in the CYP7B1 gene encoding the oxysterol 7-?-hydroxylase involved in bile acid synthesis in the liver. Lack of CYP7B1 leads to an accumulation of its oxysterol substrates, in particular 25-hydroxycholesterol and 27-hydroxycholesterol that are able to cross the blood-brain barrier and have neurotoxic properties. A potential therapeutic strategy for SPG5 is the replacement of CYP7B1 by administration of mRNA. Here, we studied the intravenous application of formulated mouse and human CYP7B1 mRNA in mice lacking the endogenous Cyp7b1 gene. A single-dose injection of either mouse or human CYP7B1 mRNA led to a pronounced degradation of oxysterols in liver and serum within 2 days of treatment. Pharmacokinetics indicate a single injection of human CYP7B1 mRNA to be effective in reducing oxysterols for at least 5 days. Repetitive applications of mRNA were safe for at least 17 days and resulted in a significant reduction of neurotoxic oxysterols not only in liver and serum but also to some extent in the brain. Our study highlights the potential to use mRNA as a novel therapy to treat patients with SPG5 disease.
| S-EPMC6888748 | biostudies-literature