Lafora progressive myoclonus epilepsy: glycogen storage disease vs neurodegenerative disease.

Neurology 2012;79:21–22 Two disease mechanisms operate in Lafora progressive myoclonus epilepsy (Lafora PME) to produce 3 phenotypes (epilepsy, rapid neurologic deterioration, and Lafora polyglucosan inclusion bodies). These 2 disease mechanisms are 1) an error in glycogen metabolism and 2) neurodegeneration. The question is, which comes first and which is primary and more important in disease production? In this issue of Neurology, Girard et al.1 support the concept of Lafora PME as an error in glycogen metabolism. They ask why polyglucosans accumulate in the somadendritic compartment in Lafora PME and produce epilepsy and why, by contrast, polyglucosans accumulate in axons/axon hillocks in adult polyglucosan body disease (APBD) and produce an axonopathy without epilepsy—in spite of the fact that polyglucosan of Lafora PME is identical to polyglucosan of APBD. Girard et al. hypothesize that the reason is phosphorylation. As a corollary to this hypothesis, they posit that phosphorylated polyglucosans are the primary cause of Lafora PME. Because of a deleted or dysfunctional mutated laforin, whose phosphatase or dephosphorylation function is located in its exon 1, polyglucosan in Lafora PME stays phosphorylated (figure e-1 on the Neurology Web site at www.neurology.org). Polyglucosan in APBD is not phosphorylated, having been formed by mutations in the glycogen branching enzyme (GBE1). Nonphosphorylated polyglucosan is free to migrate from the somadendritic compartment to the axon. In their test of this hypothesis, they used dextran, a poorly branched nonphosphorylated polyglucosan produced by fermenting bacteria as a surrogate for Lafora or APBD polyglucosan. Further, they used an animal model of Lafora PME, the epm2a / mouse. They injected either phosphorylated dextran or dextran into wild-type or Lafora mice, and showed that phosphorylated dextran only prevented polyglucosan migration from cell soma and dendrites to distal axons.1 To understand the significance of these experiments, the 2 disease mechanisms in Lafora PME are discussed. LAFORA PME AS A GLYCOGEN STORAGE DISEASE Laforin/dual specificity phosphatase is the gene product of EPM2A, mutated in 70% of patients with Lafora PME. Laforin normally acts as a glycogen phosphatase and corrects an error produced by glycogen synthase. The primary action of glycogen synthase is elongation of glycogen by adding glucose residues, packing 55,000 glucose molecules per glycogen, which maintains solubility. In what is probably a catalytic error, glycogen synthase also incorporates a phosphate into glycogen via the B-phosphate of its substrate UDP-glucose, at a rate of 1 phosphate per approximately 10,000 glucose residues.2 As a phosphatase, laforin normally removes phosphate from glycogen, correcting the error of glycogen synthase and preventing formation of phosphorylated, poorly branched insoluble glycogen polymers (Lafora polyglucosan bodies). Another function of laforin is to work with malin/E3 ubiquitin ligase, the gene product of EPM2B, the second disease-causing gene, responsible for approximately 27% of Lafora PME. Laforin and malin in concert cause proteasome-dependent degradation of PTG, a scaffold adaptor protein in exon 4 of laforin (figure e-1). Protein targeting glycogen (PTG) binds and targets glycogen and the enzymes involved in glycogen synthesis.3 This includes bringing protein phosphatase 1 to glycogen synthase, activating this enzyme, which then synthesizes glycogen. PTG also normally brings glycogen synthase to laforin. Thus, the laforin-malin complex, by degrading PTG, ensures a blockade of neuronal glycogen synthesis under normal conditions. Consequently, there is no glycogen in neurons under normal conditions. In the presence of a mutated laforin or malin, PTG is not degraded, the enzyme machinery for glycogen synthesis is anchored to PTG, and excessive less soluble glycogen with fewer -1,6 branchpoints is formed and deposited in neurons and cell death results.3,4 To disable the function of glycogen synthase, Turnbull et al.5 genetically removed PTG in epm2a / mice. Polyglucosan inclusions were dramatically reduced, Seepage100