Advances in lafora progressive myoclonus epilepsy.
Abstract Lafora progressive myoclonus epilepsy is an autosomal recessive, fatal, generalized polyglucosan storage disorder that occurs in childhood or adolescence with stimulus sensitive epilepsy (resting and action myoclonias, grand mal, and absence), dementia, ataxia and rapid neurologic deterioration. Mutations in EPM2A/laforin cause 58% of cases and mutations in EPM2B/malin cause 35% of cases. Accumulating evidence points to Lafora disease as primarily a disorder of cell death with impaired clearance of misfolded proteins, as shown by ubiquitin-positive aggresomes in HeLa cells transfected with mutated laforin, ubiquitin-positive polyglucosan inclusion bodies, and malin/E3 ubiquitin ligase polyubiquitination of laforin. How polyglucosan inclusion bodies accumulate is still a mystery. Polyglucosan accumulates hypothetically because of an overactive polyglucosan biosynthetic pathway or a breakdown in polyglucosan degradation. Five separate laboratories are looking for the biochemical pathways that connect laforin and malin to polyglucosan synthesis or degradation. A curative therapy for human Lafora disease with laforin replacement therapy using neutral pegylated immunoliposomes is being investigated.
Delgado-Escueta
Antonio V
AV
Comprehensive Epilepsy Program, Epilepsy Genetics/Genomics Laboratories, VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, West Los Angeles, CA 90073, USA. escueta@ucla.edu
D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005936:Glucans / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D020192:Lafora Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D005936:Glucans; D025801:Ubiquitin; D006003:Glycogen; C083094:polyglucosan; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human