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Myoclonic epilepsy of Lafora (R-HSA-3785653)

Species Homo sapiens

Summation

Lafora disease is a progressive neurodegenerative disorder with onset typically late in childhood, characterized by seizures and progressive neurological deterioration and death within ten years of onset. Recessive mutations in EPM2A (laforin) and NHLRC1 (malin) have been identified as causes of the disease. The disease is classified here as one of glycogen storage as EPM2A (laforin) and NHLRC1 (malin) regulate normal glycogen turnover and defects in either protein are associated with the formation of Lafora bodies, accumulations of abnormal, insoluble glycogen molecules in tissues including brain, muscle, liver, and heart (Ramachandran et al. 2009; Roach et al. 2012). Consistent with a central role for glycogen accumulation in the disease, reduced (Turnbull et al. 2011) or absent (Pederson et al. 2013) glycogen synthase activity prevents Lafora Disease in mouse models.

Type 2A disease. EPM2A (laforin) associated with cytosolic glycogen granules, normally catalyzes the removal of the phosphate groups added rarely but consistently to growing glycogen molecules (Tagliabracci et al. 2011). Defects in this catalytic activity lead to the formation of phosphorylated glycogen molecules that are insoluble and that show abnormal branching patterns (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011).

Type 2B disease. NHLRC1 (malin) normally mediates polyubiquitination of EPM2A (laforin) and PPP1R3C (PTG). The two polyubiquitinated proteins are targeted for proteasome-mediated degradation, leaving a glycogen-glycogenin particle associated with glycogen synthase. In the absence of NHLRC1 activity, EPM2A and PPP1R3C proteins appear to persist, associated with the formation of abnormal, stable glycogen granules (Lafora bodies) (Chan et al. 2003; Gentry et al. 2005). In NHLRC1 knockout mice PPP1R3C levels are unchanged rather than increased, suggesting that NHLRC1 does not target PPP1R3C for degradation. However, EPM2A protein levels are increased in this knockout consistent with NHLRC1's proposed role (DePaoli-Roach et al. 2010).

Locations in the PathwayBrowser
Diseases
Name Identifier Synonyms
glycogen storage disease 2747 [glycogenosis]
Literature References
pubMedId Title Journal Year
12958597 Mutations in NHLRC1 cause progressive myoclonus epilepsy Nat. Genet. 2003
20538597 Genetic depletion of the malin E3 ubiquitin ligase in mice leads to lafora bodies and the accumulation of insoluble laforin J. Biol. Chem. 2010
15930137 Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin Proc. Natl. Acad. Sci. U.S.A. 2005
9771710 Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy Nat. Genet. 1998
23913475 Inhibiting glycogen synthesis prevents lafora disease in a mouse model Ann. Neurol. 2013
19469843 The autosomal recessively inherited progressive myoclonus epilepsies and their genes Epilepsia 2009
22248338 Glycogen and its metabolism: some new developments and old themes Biochem. J. 2012
9931343 A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2) Hum. Mol. Genet. 1999
21356517 Phosphate incorporation during glycogen synthesis and Lafora disease Cell Metab. 2011
21552327 PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease PLoS Genet. 2011
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