Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Autosomal recessive spinocerebellar ataxia type 4 with a VPS13D mutation: A case report.

ABSTRACT:

Background

Autosomal recessive spinocerebellar ataxia type 4 (SCAR4) is a type of SCA that is a group of hereditary diseases characterized by gait ataxia. The main clinical features of SCAR4 are progressive cerebellar ataxia, pyramidal signs, neuropathy, and macrosaccadic intrusions. To date, many gene dysfunctions have been reported to be associated with SCAR4.

Case summary

Here, we report a novel compound heterozygous mutation, c.3288delA (p.Asp1097ThrfsTer6), in the VPS13D gene in a young female Chinese patient. The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital, including ataxia, neuropathy, and positive pyramidal signs. She was then diagnosed with SCAR4 and went home with symptomatic schemes.

Conclusion

SCAR4 is a hereditary disease characterized by ataxia, pyramidal signs, neuropathy, and macrosaccadic intrusions. We report a novel compound heterozygous mutation, c.3288delA (p.Asp1097ThrfsTer6), in the VPS13D gene, which enriches the gene mutation spectrum and provides additional information about SCAR4.

SUBMITTER: Huang X

PROVIDER: S-EPMC8771376 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Autosomal Recessive Spinocerebellar Ataxia Type 10: A Report of a New Case in Japan.

Project description:Autosomal recessive spinocerebellar ataxia of type 10 (SCAR10) is a very rare neurodegenerative disease caused by mutations in the TMEM16K (ANO10) gene. This disorder is characterized by slowly progressive cerebellar ataxia and pyramidal signs inconstantly associated with cognitive decline, polyneuropathy, epilepsy, and vesicorectal dysfunction. To date, more than 40 cases have been reported in Europe. In contrast, only three cases have been identified in Asian countries. We herein report the third Japanese case of SCAR10 harboring a novel homozygous deletion mutation (c.616delG, p.Glu206Lysfs*17). This case presented with adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline.

| S-EPMC9449628 | biostudies-literature

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient.

Project description:BackgroundSpinocerebellar ataxias (SCAs) are heterogeneous diseases characterized by progressive cerebellar ataxia associated with dysarthria, oculomotor abnormalities, and mental impairment. To identify the causative gene, we performed exome sequencing on a Japanese patient clinically diagnosed with recessive SCA.MethodThe patient is a 37-year-old Japanese woman with consanguineous parents. The head magnetic resonance imaging (MRI) showed cerebellar atrophy and T1 low/T2 high intensity at the bilateral inferior olives. Single-nucleotide polymorphism (SNP) genotyping and next-generation sequencing were performed, and the variants obtained were filtered and prioritized.ResultsAfter these manipulations, we identified a homozygous nonsense mutation of the TTC19 gene (p.Q277*). TTC19 has been reported to be a causative gene of a neurodegenerative disease in Italian and Portuguese families and to be involved in the pathogenesis of mitochondrial respiratory chain complex III (cIII) deficiency. This report is the first description of a TTC19 mutation in an Asian population. Clinical symptoms and neuroimaging are consistent with previous reports. The head MRI already showed abnormal features four years before her blood lactate and pyruvate levels were elevated.ConclusionsWe should consider the genetic analysis of TTC19 when we observe such characteristic MRI abnormalities. Genes associated with mitochondrial function cause many types of SCAs; the mutation we identified should help to elucidate the pathology of these disorders.

| S-EPMC3890717 | biostudies-literature

Autosomal recessive spinocerebellar ataxia 20: Report of a new patient and review of literature.

Project description:Inherited ataxias are an extremely heterogeneous group of disorders. Autosomal recessive spinocerebellar ataxia 20 (SCAR20) is a recently described disorder characterized by intellectual disability, ataxia, coarse facial features, progressive loss of Purkinje cells in the cerebellum and often hearing loss and skeletal abnormalities. Mutations in the gene SNX14, which plays an important role in autophagy, have been found to cause SCAR20. The unique clinical findings of progressive coarsening of facial features makes the clinical phenotype recognizable among the various hereditary ataxias. Here we report on a child with a novel missense mutation in the SNX14 gene that appears to be debilitating for protein conformation, function and review the previously reported cases from 15 families.

| S-EPMC5241222 | biostudies-literature

Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia.

Project description:Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.

| S-EPMC3424653 | biostudies-literature

Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation.

Project description:Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.

| S-EPMC3155161 | biostudies-literature

Case Report: Late-Onset Autosomal Recessive Cerebellar Ataxia Associated With <i>SYNE1</i> Mutation in a Chinese Family.

Project description:Autosomal recessive cerebellar ataxia type 1 (ARCA-1), also known as autosomal recessive spinocerebellar ataxia type 8 (SCAR8), is caused by spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene mutation. Nesprin-1, encoded by SYNE1, is widely expressed in various tissues, especially in the striated muscle and cerebellum. The destruction of Nesprin-1 is related to neuronal and neuromuscular lesions. It has been reported that SYNE1 gene variation is associated with Emery-Dreifuss muscular dystrophy type 4, arthrogryposis multiplex congenita, SCAR8, and dilated cardiomyopathy. The clinical manifestations of SCAR8 are mainly characterized by relatively pure cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction. Some affected people may also display cerebellar cognitive affective syndrome. It is conventionally held that the age at the onset of SCAR8 is between 6 and 42 years (the median age is 17 years). Here, we report a pedigree with SCAR8 where the onset age in the proband is 48 years. This case report extends the genetic profile and clinical features of SCAR8. A new pathogenic site (c.7578del; p.S2526Sfs*8) located in SYNE1, which is the genetic cause of the patient, was identified via whole exome sequencing (WES).

| S-EPMC8905644 | biostudies-literature

Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

Project description:The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16.

| S-EPMC5827432 | biostudies-literature

Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?

Project description:Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3' end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1-/- mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1-/- mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant.

| S-EPMC2080798 | biostudies-literature

SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20.

Project description:Mutations in SNX14 cause the autosomal recessive cerebellar ataxia 20 (SCAR20). Mutations generally result in loss of protein although several coding region deletions have also been reported. Patient-derived fibroblasts show disrupted autophagy, but the precise function of SNX14 is unknown. The yeast homolog, Mdm1, functions in endoplasmic reticulum (ER)-lysosome/vacuole inter-organelle tethering, but functional conservation in mammals is still required. Here, we show that loss of SNX14 alters but does not block autophagic flux. In addition, we find that SNX14 is an ER-associated protein that functions in neutral lipid homeostasis and inter-organelle crosstalk. SNX14 requires its N-terminal transmembrane helices for ER localization, while the Phox homology (PX) domain is dispensable for subcellular localization. Both SNX14-mutant fibroblasts and SNX14KO HEK293 cells accumulate aberrant cytoplasmic vacuoles, suggesting defects in endolysosomal homeostasis. However, ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating that it is not a prerequisite for ER-endolysosomal tethering. Further investigation of SNX14- deficiency indicates general defects in neutral lipid metabolism. SNX14KO cells display distinct perinuclear accumulation of filipin in LAMP1-positive lysosomal structures indicating cholesterol accumulation. Consistent with this, SNX14KO cells display a slight but detectable decrease in cholesterol ester levels, which is exacerbated with U18666A. Finally, SNX14 associates with ER-derived lipid droplets (LD) following oleate treatment, indicating a role in ER-LD crosstalk. We therefore identify an important role for SNX14 in neutral lipid homeostasis between the ER, lysosomes and LDs that may provide an early intervention target to alleviate the clinical symptoms of SCAR20.

| S-EPMC5961352 | biostudies-literature

Heterozygous pathogenic variants in CWF19L1 in a Chinese family with spinocerebellar ataxia, autosomal recessive 17.

Project description:BackgroundCWF19L1 is responsible for spinocerebellar ataxia, autosomal recessive 17, which presents with cerebellar ataxia, and atrophy. Here, we report novel compound heterozygous variants of CWF19L1 in a Chinese family with progressive ataxia and mental retardation of unknown etiology by analyzing clinical characteristics and genetic variations.MethodsClinical profiles and genomic DNA extracts of family members were collected. Whole-exome and Sanger sequencing were performed to detect associated genetic variants. Pathogenicity prediction and conservation analysis of the identified variants were performed using bioinformatics tools.ResultsWe identified heterozygous variants at the invariant +2 position (c.1555_c.1557delGAG in exon 14 and c.1070G > T in exon 11) of the CWF19L1 gene. Two novel heterozygous variants of the CWF19L1 gene were identified in the CWF19L1 gene associated with autosomal recessive cerebellar ataxia.ConclusionOur results suggest that CWF19L1 variants may be a novel cause of recessive ataxia with developmental delay. Whole-exome sequencing is an efficient tool for screening variants associated with the disease. This case report may help diagnose and identify the causes of other ataxias, leading to novel therapies, especially in China. This finding enriches the variant spectrum of the CWF19L1 gene and lays the foundation for future studies on the correlation between genotype and phenotype.

| S-EPMC9757004 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data