Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027066 (myoclonus)
 4,275 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic progressive myoclonus epilepsies (PMEs) are clinically characterized by the triad of stimulus sensitive myoclonus (segmental lightning like muscular jerks), epilepsy (grand mal and absences) and progressive neurologic deterioration (dementia, ataxia, and various neurologic signs depending on the cause). Etiologically heterogenous, PMEs are rare and mostly autosomal recessive disorders, with the exception of autosomal dominant dentatorubral-pallidoluysian atrophy and mitochondrial encephalomyopathy with ragged red fibers (MERRF). In the last five years, specific mutations have been defined in Lafora disease (gene for laforin or dual specificity phosphatase in 6q24), Unverricht-Lundborg disease (cystatin B in 21q22.3), Jansky-Bielschowsky ceroid lipofuscinoses (CLN2 gene for tripeptidyl peptidase 1 in 11q15), Finnish variant of late infantile ceroid lipofuscinoses (CLN5 gene in 13q21-32 encodes 407 amino acids with two transmembrane helices of unknown function), juvenile ceroid lipofuscinoses or Batten disease (CLN3 gene in 16p encodes 438 amino acid protein of unknown function), a subtype of Batten disease and infantile ceroid lipofuscinoses of the Haltia-Santavuori type (both are caused by mutations in palmitoyl-protein thiosterase gene at 1p32), dentadorubropallidoluysian atrophy (CAG repeats in a gene in 12p13.31) and the mitochondrial syndrome MERRF (tRNA Lys mutation in mitochondrial DNA). In this review, we cover mainly these rapid advances.
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PMID:Advances in the genetics of progressive myoclonus epilepsy. 1157 33

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.
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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

Progressive myoclonus epilepsy of Lafora type (LD, MIM 254780) is a fatal autosomal recessive disorder characterized by the presence of progressive neurological deterioration, myoclonus, epilepsy and polyglucosan intracellular inclusion bodies, called Lafora bodies. Lafora bodies resemble glycogen with reduced branching, suggesting an alteration in glycogen metabolism. Linkage analysis and homozygosity mapping localized EPM2A, a major gene for LD, to chromosome 6q24. EPM2A encodes a protein of 331 amino acids (named laforin) with two domains, a dual-specificity phosphatase domain and a carbohydrate binding domain. Here we show that, in addition, laforin interacts with itself and with the glycogen targeting regulatory subunit R5 of protein phosphatase 1 (PP1). R5 is the human homolog of the murine Protein Targeting to Glycogen, a protein that also acts as a molecular scaffold assembling PP1 with its substrate, glycogen synthase, at the intracellular glycogen particles. The laforin-R5 interaction was confirmed by pull-down and co-localization experiments. Full-length laforin is required for the interaction. However, a minimal central region of R5 (amino acids 116-238), including the binding sites for glycogen and for glycogen synthase, is sufficient to interact with laforin. Point-mutagenesis of the glycogen synthase-binding site completely blocked the interaction with laforin. The majority of the EPM2A missense mutations found in LD patients result in lack of phosphatase activity, absence of binding to glycogen and lack of interaction with R5. Interestingly, we have found that the LD-associated EPM2A missense mutation G240S has no effect on the phosphatase or glycogen binding activities of laforin but disrupts the interaction with R5, suggesting that binding to R5 is critical for the laforin function. These results place laforin in the context of a multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin is involved in the regulation of glycogen metabolism.
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PMID:Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. 1453 30

Lafora disease (LD) is an autosomal recessive inherited form of progressive myoclonic epilepsy with dementia and ataxia, usually presenting in the second decade of life and inexorably progressing until death. Neuropathological hallmarks are Lafora bodies, intracytoplasmic inclusions that can be found in neurons and in other tissues. LD gene (EPM2A), mapping on chromosome 6, encodes for a tyrosine phosphatase protein called laforin. However, up to 20% cases of LD are not genetically linked to chromosome 6. We report two sisters affected from bioptically diagnosed LD but without evidence of EPM2A mutation. Although familial cases of LD are already reported in literature, our observation leads to some considerations on clinical-electrophysiological evolution as well as to remark the genetic heterogeneity of this condition. In addition, we report the good effect of the Levetiracetam for the treatment of myoclonus in these patients, also demonstrated by the electrophysiological findings.
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PMID:Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters. 1464 20

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.
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PMID:[Molecular genetics of epilepsy]. 1565 14

Epilepsy of progressive myoclonus type 2 gene A (EPM2A) encodes a dual specificity protein phosphatase called Laforin. Laforin is also a tumor suppressor that dephosphorylates GSK3beta at the critical Ser9 position and regulates Wnt signaling. The epilepsy-causing mutations have a deleterious effect on phosphatase activity, regardless of whether they locate in the carbohydrate-binding domain (CBD) at the N terminus or the dual specificity phosphatase domain (DSPD) at the C terminus. How mutations outside the DSPD reduce the phosphatase activity of Laforin remains unexplained. Here we report that Laforin expressed in mammalian cells forms dimers that are highly resistant to SDS treatment. Deleting CBD completely abolished the dimerization and phosphatase activity of Laforin. Moreover, all of the naturally occurring Laforin mutations tested impaired laforin GSK3beta dephosphorylation at Ser9 dimerization, and beta-catenin accumulation in nucleus. Our results demonstrate a critical role of dimerization in Laforin function and suggest an important new dimension in protein phosphatase function and in molecular pathogenesis of Lafora's disease.
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PMID:Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling. 1697 87

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.
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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.
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PMID:[Lafora's disease presenting with progressive myoclonus epilepsy]. 1803 35

PRO: In the past decade, genotyping has started to help the neurologic practitioner treat patients with three types of epilepsy causing mutations, namely (1) SCN1A, a sodium channel gene mutated in Dravet's sporadic severe myoclonic epilepsy of infancy (SMEI and SMEB); (2) laforin (dual specificity protein phosphatase) and malin (ubiquitin E3 ligase) in Lafora progressive myoclonic epilepsy (PME); and (3) cystatin B in Unverricht-Lundborg type of PME. Laforin, malin, and cystatin B are non-ion channel gene mutations that cause PME. Genotyping ensures accurate diagnosis, helps treatment and genetic counseling, psychological and social help for patients and families, and directs families to organizations devoted to finding cures for specific epilepsy diseases. In SCN1A and cystatin B mutations, treatment with sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) should be avoided. Because of early and correct diagnosis by genotyping of SCN1A mutations, the avoidance of sodium channel blockers, and aggressive treatment of prolonged convulsive status, there is hope that Dravet's syndrome may not be as severe as observed in all past reports. Genotyping also identifies nonsense mutations in Lafora PME. Nonsense mutations can be corrected by premature stop codon readthrough drugs such as gentamicin. The community practitioner together with epilepsy specialists in PME can work together and acquire gentamicin (Barton-Davis et al., 1999) for "compassionate use" in Lafora PME, a generalized lysosome multiorgan storage disorder that is invariably fatal. In Unverricht-Lundborg PME, new cohorts with genotyped cystatin B mutations have led to the chronic use of antioxidant N-acetylcysteine and combination valproate clobazam or clonazepam plus antimyoclonic drugs topiramate, zonisamide, piracetam, levetiracetam, or brivaracetam. These cohorts have minimal ataxia and no dementia, questioning whether the syndrome is truly progressive. In conclusion, not only is genotyping a prerequisite in the diagnosis of Dravet's syndrome and the progressive myoclonus epilepsies, but it also helps us choose the correct antiepileptic drugs to treat seizures in Dravet's syndrome and Unverricht-Lundborg PME. Genotyping also portends a brighter future, helping us to reassess the true course, severity, and progressive nature of Dravet's syndrome and Unverricht-Lundborg PME and helping us craft a future curative treatment for Dravet's syndrome and Lafora disease. Without the genotyping diagnosis of epilepsy causing mutations we are stuck with imprecise diagnosis and symptomatic treatment of seizures. CON: Genotyping of epilepsy may help to better understand the genetics of epilepsy, to establish an etiology in a patient with epilepsy, to provide genetic counseling, and to confirm a clinical diagnosis. However, critical analysis reveals that genotyping does not contribute to an improved treatment for the patients. In order to improve treatment, genotyping would have to (1) improve our ability to select the drug of choice for a given epilepsy or epileptic syndrome; (2) improve our ability to predict the individual risk of adverse reactions to certain drugs; (3) improve our ability to avoid unnecessary treatments or treatments that could aggravate seizures. Many example illustrate the lack of impact of genetic information on the treatment outcome: we do not treat Dravet syndrome more successfully since SCN1A testing became available; we do not treat Lafora disease more successfully since testing for laforin and malin became available; we do not need to know the genetic nature of Unverricht-Lundborg disease or test for the cystatin B mutation in order to select or avoid certain drugs; we do not treat Rett syndrome more successfully since MECP2 testing became available; we do not treat JME more successfully since we know its genetic origin; we do not treat autosomal dominant nocturnal frontal lobe epilepsy more successfully since we know its genetic origin and can test for its mutation. The clinical characteristics as well as the response to treatment of these epilepsy syndromes have been well established before genotyping became available. It can not be argued that genotyping is necessary for establishing a diagnosis or ensure accurate diagnosis. Since not all individuals with given syndromes have been shown to have the corresponding mutation, the clinical diagnosis must have been based on well-established clinical criteria. In addition, the presence or absence of the mutation in a given patient has never been shown to specifically predict the response to any form of treatment, positive or negative. Finally, the appropriate psychological and social help in a given patient will not depend on the identification of a mutation. This does not leave any role for genotyping in epilepsy for the sole reason of improving treatment of the patient. Claiming that the result of genotyping predicts optimal treatment in certain epilepsies is equivalent to stating that genotyping for diabetes has become available and that, based on this breakthrough, insulin can now be selected as the treatment of choice in those who test positive.
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PMID:Debate: Does genetic information in humans help us treat patients? PRO--genetic information in humans helps us treat patients. CON--genetic information does not help at all. 1908 13

Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The condition is characterized by epilepsy, myoclonus and dementia. Diagnostic findings on MRI and neurophysiological testing are not definitive and biopsy or genetic studies may be required. Therapy in Lafora disease is currently limited to symptomatic management of the epilepsy, myoclonus and intercurrent complications. With a greater understanding of the pathophysiological processes involved, there is justified hope for future therapies.
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PMID:Lafora disease: epidemiology, pathophysiology and management. 2052 95


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