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).