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.

Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

“…Glycogen is known to contain minor amounts of covalently attached phosphate, and excessive accumulation of covalent phosphate is thought to underlie Lafora disease, a devastating form of myoclonus epilepsy that is ultimately fatal (8)(9)(10). Where the phosphate is located on the glucose residues with glycogen is an active area of investigation, as is the mechanism by which it is introduced.…”

Autophagy and neurodegeneration

“…80). LB accumulation may be partly the result of altered carbohydrate metabolism (81). However, data from kin RBR E3 ubiquitin protein ligase (PARK2, also known as Parkin) in mitophagy (reviewed in ref.…”

Starch Binding Domain-containing Protein 1/Genethonin 1 Is a Novel Participant in Glycogen Metabolism

“…Like amylopectin, glycogen contains small amounts of covalent phosphate, one phosphate per 650 -1500 glucose residues, whose function is poorly understood (21,22). Lafora disease is a progressive myoclonus epilepsy that is characterized by teenage-onset seizures leading to death usually within 10 years (35)(36)(37). Lafora disease is characterized by the accumulation of Lafora bodies, deposits that contain poorly branched glycogen.…”