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

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.
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PMID:An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures. 1564 21

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.
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PMID:Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. 1613 45

We report a family with four brothers affected by Lafora disease (LD). Mean age at onset was 19.5 years (range, 17-21). In all cases, the initial obvious symptoms were diffuse myoclonus and occasional generalized tonic-clonic seizures (GTCSs), followed by cognitive difficulties. Severity of myoclonus, seizure diaries, and neurologic and neuropsychological status were finally evaluated in March 2005. The duration of follow-up was >10 years for three subjects. Daily living activities and social interaction were preserved in all cases and, overall, the progression of the disease was slow. Genetic study revealed the homozygous mutation D146N in the EPM2B gene. We suggest that this mutation may be associated with a less severe LD phenotype.
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PMID:Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. 1619 Sep 47

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

A 22-year-old girl presented with convulsive status epilepticus and a previous history of recurrent seizures, myoclonus, ataxia and impaired cognitive functions. Neurological examination revealed rest and action-induced myoclonus, pyramidal signs and opposition hypertonia. Testing revealed severe metabolic acidosis, elevated transaminases and creatine kinase, and respiratory insufficiency. After intubation and ventilation, thiopental was introduced but the patient's condition worsened dramatically with death in a few hours. Autopsy showed profuse periodic acid-Schiff (PAS) positive intracellular inclusions in the CNS (Lafora bodies), most abundant in thalamus, cerebellum, and brainstem, as well as in other organs. Genetic testing revealed a homozygous missense mutation (c.205C > G, P69A) in the EPM2B (NHLRC1) gene, confirming the diagnosis of progressive myoclonic epilepsy Lafora-type.
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PMID:22-year-old girl with status epilepticus and progressive neurological symptoms. 1974 44

We report a patient with congenital generalized lipodystrophy who had suffered from seizures, myoclonus, ataxia and cognitive decline since late childhood. Lafora disease was diagnosed based on skin biopsy results, which revealed pathognomonic Lafora bodies. The results of genetic analysis for mutations in EPM2A and EPM2B genes were negative. This is the first case report describing an association between congenital generalized lipodystrophy and Lafora disease. Further studies focusing on the relationship between these two diseases and the identification of a third locus for Lafora disease are needed.
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PMID:Lafora disease and congenital generalized lipodystrophy: a case report. 1995 52

Myoclonic epilepsy of Lafora (EPM2) is a severe autosomal recessive disorder. The onset in adolescence, generalized seizures, severe myoclonus, dementia and a rapid malignant course with death in 4-8 years after the onset are characteristic features of EPM2. The disease has a specific pathological feature, intracellular polyglucosan inclusions (Lafora bodies) in the brain, liver, skin and muscles. Two genetic forms are known, one of which (EPM2A) is caused by mutations in the laforin gene and another (EPM2B)--by mutations in the malin gene. We report a case of EPM2A in a 17-year-old girl of mixed Russian-Ukrainian ethnicity. The disease lasted for almost four years by the time of the examination but the girl still had no dementia. A previously described laforin mutation Tyr86Stop in the homozygous state was detected and Lafora bodies were found in the skin and muscles. Various anticonvulsants produced no effect or a slight and unstable effect. In the following several months, the disease progressed quickly, the girl became severely disabled and demented and died in 19 years old, 5.5 years after the disease onset. This is a first Russian case confirmed by DNA testing.
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PMID:[Myoclonic epilepsy of Lafora: a case report]. 2087 69

Lafora disease is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. Here, we report three Lafora families with two novel pathogenic mutations (C46Y and L261P) and two recurrent mutations (P69A and D146N) in NHLRC1. Investigation of their functional consequences in cultured mammalian cells revealed that malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. Abnormal accumulation of intracellular glycogen was observed with all malin mutants, reminiscent of the polyglucosan inclusions (Lafora bodies) present in patients with Lafora disease.
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PMID:Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism. 2150 99

Lafora disease (LD) is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. 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 review also outlines important patents related to Lafora disease.
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PMID:Lafora progressive myoclonus epilepsy: recent insights into cell degeneration. 2236 17

Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. It is characterized by the presence of polyglucosan intracellular inclusion bodies (Lafora bodies) in brain and other tissues. Targeted disruption of Epm2a or Epm2b genes in mice produced widespread neuronal degeneration and accumulation of Lafora bodies in neuronal and nonneuronal tissues. Here we analyzed the neurologic alterations produced by disruption of the laforin gene in Epm2a mice and compared them to those in malin-deficient mice. Both Epm2a and Epm2b mice showed altered motor activity, impaired motor coordination, abnormal hind limb clasping, and episodic memory deficits. Epm2a mice also had tonic-clonic seizures, whereas both Epm2a and Epm2b mice had spontaneous single spikes, spike-wave, polyspikes, and polyspike-wave complexes with correlated myoclonic jerks. Neurologic alterations observed in the mutants were comparable and correlated with the accumulation of abundant Lafora bodies in the cerebral cortex, the hippocampus, the basal ganglia, the cerebellum, and the brainstem, suggesting that these inclusions could cause cognitive and behavioral deterioration. Thus, both Epm2a and Epm2b mice exhibit many pathologic aspects seen in patients with Lafora disease and may be valuable for the study of this disorder.
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PMID:Laforin and malin deletions in mice produce similar neurologic impairments. 2248 59


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