Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy
We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted “next-generation” sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linkedIQSEC2 gene NM_001111125.2:...
Source: Neurogenetics - June 19, 2020 Category: Genetics & Stem Cells Source Type: research
Is NIPA1-associated hereditary spastic paraplegia always ‘pure’? Further evidence of motor neurone disease and epilepsy as rare manifestations
We present a patient with childhood idiopathic generalised epilepsy (IGE) who later developed HSP. She rapidly deteriorated 27 years later with clinically definite amyotrophic lateral sclerosis (ALS). Her family history included HSP, IGE and motor neurone disease. Genetic testing identified a pathogenic variant in theNIPA1 gene associated with spastic paraplegia 6 (SPG6). This case provides the first description ofNIPA1 in a family with epilepsy, ALS and thus complex HSP. (Source: Neurogenetics)
Source: Neurogenetics - June 4, 2020 Category: Genetics & Stem Cells Source Type: research
Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report
We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation inMTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis ofMTMR2-related neuropathies. (Source: Neurogenetics)
Source: Neurogenetics - June 2, 2020 Category: Genetics & Stem Cells Source Type: research
A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures
AbstractDeficiency of the endoplasmic reticulum transmembrane proteinARV1 leads to epileptic encephalopathy in humans and in mice.ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeastarv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins. GPI anchors are post-translational modifications, enabling proteins to travel from the endoplasmic reticulum (ER) through the Golgi and to attach to plasma membra...
Source: Neurogenetics - May 26, 2020 Category: Genetics & Stem Cells Source Type: research
Genetic Creutzfeldt-Jakob disease in Sardinia: a case series linked to the PRNP R208H mutation due to a single founder effect
AbstractIn genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208HPRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our ...
Source: Neurogenetics - May 25, 2020 Category: Genetics & Stem Cells Source Type: research
Expanding the genotype-phenotype spectrum of ISCA2 -related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival
This report expands the clinical spectrum ofISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation. (Source: Neurogenetics)
Source: Neurogenetics - May 17, 2020 Category: Genetics & Stem Cells Source Type: research
Rare copy number variations of planar cell polarity genes are associated with human neural tube defects
This study demonstrates that de novo CNVs in PCP genes, notably deletions inVANGL1 and gains inDVL2, could contribute to the risk of NTDs. (Source: Neurogenetics)
Source: Neurogenetics - May 8, 2020 Category: Genetics & Stem Cells Source Type: research
Oligogenicity, C9orf72 expansion, and variant severity in ALS
Abstract“Oligogenic inheritance” is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sc lerosis (ALS). We sequenced ALS-associated genes inC9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly hi...
Source: Neurogenetics - May 7, 2020 Category: Genetics & Stem Cells Source Type: research
Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain
In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory res ponse may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate. (Source: Neurogenetics)
Source: Neurogenetics - May 5, 2020 Category: Genetics & Stem Cells Source Type: research
Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213 , a susceptibility factor for moyamoya disease
AbstractHumanRNF213, which encodes the protein mysterin, is a known susceptibility gene for moyamoya disease (MMD), a cerebrovascular condition with occlusive lesions and compensatory angiogenesis. Mysterin mutations, together with exposure to environmental trigger factors, lead to an elevated stroke risk since childhood. Mysterin is induced during cell stress, to function as cytosolic AAA+ ATPase and ubiquitylation enzyme. Little knowledge exists, in which context mysterin is needed. Here, we found that genetic ablation of several mitochondrial matrix factors, such as the peptidaseClpP, the transcription factorTfam, as we...
Source: Neurogenetics - April 27, 2020 Category: Genetics & Stem Cells Source Type: research
Adult-onset glutaric aciduria type I: rare presentation of a treatable disorder
AbstractGlutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid due to a defect in the glutaryl-CoA dehydrogenase enzyme involved in the catabolic pathways ofl-lysine,l-hydroxylysine, andl-tryptophan. Glutaryl-CoA dehydrogenase is encoded by theGCDH gene (OMIM #608801), and several mutations in this gene are known to result in GA1. GA1 usually presents in the first 18 –36 months of life with mild or severe acute encephalopathy, movement disorders, and striatal degeneration. Few cases of adult-onse...
Source: Neurogenetics - April 17, 2020 Category: Genetics & Stem Cells Source Type: research
Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1
AbstractHereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by progressive spastic paraparesis.UBAP1 was recently found to induce a rare type of HSP (SPG80). We identified a family with eight inherited spastic paraplegic patients carrying a novel heterozygous mutation c.279delG (p.S94Vfs*9) ofUBAP1. We demonstrated a lack of functional UBAP1 in these patients, resulting in the neurological disorder caused by interceptions of the ESCRT pathway. Extending from the older onset-age identified from this family, we found that comparing with the European and other populations, Asian p...
Source: Neurogenetics - March 27, 2020 Category: Genetics & Stem Cells Source Type: research
Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients
AbstractEvidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of park...
Source: Neurogenetics - March 25, 2020 Category: Genetics & Stem Cells Source Type: research
Familial analysis reveals rare risk variants for migraine in regulatory regions
We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those ori...
Source: Neurogenetics - February 18, 2020 Category: Genetics & Stem Cells Source Type: research
Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype
This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts ofKCNJ10, a gene initially associated only with the EAST/SeSAME syndrome. (Source: Neurogenetics)
Source: Neurogenetics - February 14, 2020 Category: Genetics & Stem Cells Source Type: research
