Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.
 ...
PMID:Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. 977 10

Lafora's disease is one of five inherited progressive myoclonus epilepsy syndromes. It is an autosomal-recessive disorder with onset in late childhood or adolescence. Characteristic seizures include myoclonic and occipital lobe seizures with visual hallucinations, scotomata, and photoconvulsions. The course of the disease consists of worsening seizures and an inexorable decline in mental and other neurologic functions that result in dementia and death within 10 years of onset. Pathology reveals pathognomonic polyglucosan inclusions that are not seen in any other progressive myoclonus epilepsy. Lafora's disease is one of several neurologic conditions associated with brain polyglucosan bodies. Why Lafora's polyglucosan bodies alone are associated with epilepsy is unknown and is discussed in this article. Up to 80% of patients with Lafora's disease have mutations in the EPM2A gene. Although common mutations are rare, simple genetic tests to identify most mutations have been established. At least one other still-unknown gene causes Lafora's disease. The EPM2A gene codes for the protein laforin, which localizes at the plasma membrane and the rough endoplasmic reticulum and functions as a dual-specificity phosphatase. Work toward establishing the connection between laforin and Lafora's disease polyglucosans is underway, as are attempts to replace it into the central nervous system of patients with Lafora's disease.
 ...
PMID:Lafora's disease: towards a clinical, pathologic, and molecular synthesis. 1148 92

Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.
 ...
PMID:Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. 1201 6

Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (i) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in HeLa cells. Expression of three mutant proteins (T194I, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.
 ...
PMID:Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. 1201 7

Lafora's disease is a progressive myoclonus epilepsy with onset in adolescence and a gradual decline in cognitive functions and increase in seizure intractability. We present the case of a 16-year-old with precipitous dementia within 6 months of onset. Peripheral biopsies and EPM2A mutation analysis were negative. The diagnosis could be established only by brain biopsy.
 ...
PMID:Unusual presentation of Lafora's disease. 1294 Jun 57

The authors describe three siblings born to consanguineous parents with early onset ataxia, dysarthria, myoclonic, generalized tonic clonic seizures, upward gaze palsy, extensor plantar reflexes, sensory neuropathy, and normal cognition. Direct screening excluded mutations in FRDA, TDP1,and SACS genes and at 8344, 3243, and 8993 positions of mitochondrial DNA. Linkage analysis excluded AOA-1, EPM1, EPM2A, EPM2B, CAMOS, and recessive ataxias linked to chromosome 9q34-9qter. This clinical constellation may represent a distinct form of early onset cerebellar ataxia.
 ...
PMID:An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures. 1564 21

Recent identifications of genes responsible for epilepsies are now contributing to diagnosis and treatment. Mutations of voltage-gated sodium channel genes SCN1A and SCN2A have been reported in epilepsies with a variety of phenotypes including generalized epilepsy with febrile seizures plus (GEFS +), severe myoclonic epilepsy in infancy (SMEI), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and benign familial neonatal-infantile seizures (BFNIS). We also identified a sporadic nonsense mutation of SCN2A in a patient with intractable epilepsy with severe mental decline. Lafora's disease (LD) is a fatal autosomal recessive epilepsy characterized by stimuli sensitive myoclonus, grand mal seizures, and progressive intellectual and neurological deterioration. The EPM2A gene has been reported to be responsible for LD. We found multiple disease mutations of EPM2A in LD patients, and also identified a subclass of LD who shows an early onset cognitive defect and correlated with EPM2A exon 1 mutations. We reported that the laforin protein encoded by the EPM2A gene has a dual-specificity phosphatase activity, associates with polyribosome, and interacts with the HIRIP5 protein with NifU-like domain. We recently generated and reported the EPM2A KO mice those develop neurodegeneration and other features similar to those of LD patients.
 ...
PMID:[Molecular genetics of epilepsy]. 1565 14

Progressive Myoclonus Epilepsy (PME) of the Lafora type is an autosomal recessive disease, which presents in teenage years with myoclonia and generalized seizures leading to death within a decade of onset. It is characterized by pathognomonic inclusions, Lafora bodies (LB), in neurons and other cell types. Two genes causing Lafora disease (LD), EPM2A on chromosome 6q24 and NHLRC1 (EPM2B) on chromosome 6p22.3 have been identified, and our recent results indicate there is at least one other gene causing the disease. The EPM2A gene product, laforin, is a protein tyrosine phosphatase (PTP) with a carbohydrate-binding domain (CBD) in the N-terminus. NHLRC1 encodes a protein named malin, containing a zinc finger of the RING type in the N-terminal half and 6 NHL-repeat domains in the C-terminal direction. To date 43 different variations in EPM2A and 23 in NHLRC1 are known, including missense, nonsense, frameshift, and deletions. We have developed a human LD mutation database using a new generic biological database cross-referencing platform. The database, which currently contains 66 entries is accessible on the World Wide Web (http://projects.tcag.ca/lafora). Entries can be submitted via the curator of the database or via a web-based form.
 ...
PMID:Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. 1613 45

Lafora's disease (LD) is a comparatively frequent and particularly severe type of progressive myoclonus epilepsy. Prevalence varies, LD is seen everywhere but is more common in geographic isolates and areas with high degree of inbreeding. Onset occurs during adolescence, with generalized tonic-clonic, clonic-tonic-clonic seizures, action and resting myoclonus, negative myoclonus, and focal occipital seizures with transient amaurosis. The course is marked by prominent cognitive deterioration, which can precede seizures and myoclonus, and by the progressive, relentless increase of seizures and myoclonus. Transmission is autosomal recessive. LD is genetically heterogeneous. Mutations/deletions of the EPM2A gene, localized in 1995 on 6q24, are found in 80p.cent (product: laforin), the less common EPM2B variant is on 6p22 (product: malin), but these two localizations do not account for all cases of LD. The diagnosis of LD may be suspected on the basis of the family history, age at onset, typical appearance of symptoms, rapid worsening of cognitive function, evaluation of fairly typical EEG aspects, and can easily be confirmed by axillar skin biopsy with proof of Lafora bodies (polyglucosan aggregates) in the sweat duct cells. Other biopsies, like brain biopsy, are generally not necessary. Genetic testing is useful for diagnosis but the genetic heterogeneity cannot rule out LD when none of the known mutations are detected. Genetic counselling and prenatal diagnosis are theoretically possible when the genetic anomaly has been documented in an affected member of the family. The treatment of LD remains purely symptomatic. Drugs that may aggravate myoclonus must be avoided. Psychological and social management is of utmost importance in LD. Death occurs 4 to 10 years after onset in typical forms.
 ...
PMID:[Lafora's disease (EPM2)]. 1730 72

Lafora's disease is a progressive myoclonus epilepsy and must be evocated if myoclonus, occipital seizures and progressive cognitive impairment are present. We report the case of a 14-year-old boy who suffered from several occipital seizures and two generalised seizures. The diagnosis of Lafora's disease was made six years after these inaugural symptoms because of occurrence of myoclonus, aggravation of the epilepsy with paharmacoresistance and psychic deterioration. Axila sweat gland duct biopsy was performed to conclude to the disease. A mutation was found on the gene EPM2A. Lafora's disease is a genetic autosomal-recessive pathology. Two genes have been recently identified. They code for two proteins, malin and laforin, involved in glycogen metabolism in the cellular endoplasmic reticulum. Mutations of these genes are responsible for intracytoplasmic polyglucosan inclusions called Lafora bodies and pathognomonic of the disease.
 ...
PMID:[Lafora's disease presenting with progressive myoclonus epilepsy]. 1803 35


1 2 3 4 Next >>