Clinical-scientific notes.

Neuronal distal axons have limited access to glucose, their myelin sheaths preventing direct interface with blood, and their axoplasms being at great distances from their cell bodies. Glycogen, the mammalian glucose store, is characterized by extreme branching, which allows packing 55,000 glucoses/glycogen, and maintaining solubility. In neurons, glycogen phos-phorylase, the glycogen-digesting enzyme, is located in distal axons where it can generate large amounts of glucose from glycogen. 1 Two neurologic diseases, adult polyglucosan body disease (APBD) and Lafora disease (LD), are associated with neuronal formation of poorly branched glycogen, termed polyglucosan, which precipitate and accumulate into large masses called polyglucosan or Lafora bodies. APBD is caused by mutations in the GBE1 gene encoding the glycogen branching enzyme. APBD polyglucosans appear to be subject to transport from cell body to axons, accumulating exclusively in axons and axon hillocks, with no accumulation in the somatodendritic compartment. Subcortical and spinal cord fiber tracts and peripheral nerves are replete with polyglucosans and often obstructed. Expectedly, the disease is an axonopathy (onset ϳage 50) with progressive upper and lower motor, sensory, and bladder control deficits. MRI shows diffuse subcortical signal abnormality, and nerve conduction studies and EMG axonal sensori-motor peripheral neuropathy. 2 There is no epilepsy. LD is a fatal progressive myoclonus epilepsy (onset ϳage 15), 3 with no axonopathy, caused by mutations of genes EPM2A (laforin) or EPM2B (malin). Laforin is a phosphatase that prevents accumulation of phosphate on glycogen. 5 Malin is an E3 ubiquitin ligase which regulates laforin. 4 Phosphate accumulation on glycogen leads glycogen to unfold and precipitate. 5 Glycogen synthase (GS), the enzyme that elongates glycogen, remains bound to the precipitating glycogen, while branching enzyme does not. 5 Elongation by GS without branching may explain subsequent conversion of precipitated glycogen to polyglucosan. LD polyglucosans are identical to APBD polyglucosans, except that they are phosphor-ylated. 3–5,e5 They also differ in the neuronal compartment in which they accumulate, namely cell body and dendrites, gradually replacing the cytoplasms of countless dendrites. Axons are rarely affected. Subcortical MRI signal and nerve conduction studies are normal. 3 Likely, progressive overtaking of dendritic cytoplasms underlies the progressive epilepsy of LD as does the accumulation in axons the axonopathy of APBD. 3 The standard neuronal tracer dextran is a poorly branched nonphosphorylated polyglucosan produced by fermenting bacteria. It is structurally similar to APBD and LD polyglucosans, differing in having ␣1– 6 instead of ␣1– 4 interglucosidic linkages. …