PATHOGENESIS OF LAFORA DISEASE: ARE WE THERE YET?

Abstract

Lafora disease is a fatal progressive myoclonus epilepsy syndrome with onset in teenage years. Neurons in this disease exhibit accumulations of starch-like molecules, polyglucosans, which coalesce into inclusions known as Lafora bodies. Lafora bodies preferentially form in dendrites and are present in most dendrites, often completely occupying the post-synaptic space. Polyglucosans are malformed glycogen molecules lacking the organized branching that allows normal glycogen to dissolve in the cytoplasm. Lafora disease is caused by mutations in at least two genes. The first, EPM2A, encodes the laforin starch-binding dual-specificity phosphatase. The second, EPM2B, encodes malin, the laforin-interacting ubiquitin E3 ligase. This presentation synthesizes knowledge from the extensive pathological analyses of Lafora bodies in the “pre-genetic era” with modern molecular knowledge stemming from the disease genes. It describes our current model of Lafora body formation. In this model laforin plays a central organizing role. It monitors the appearance of polyglucosans during glycogen synthesis. Once it detects polyglucosans, it initiates a multi-pronged response via malin, glycogen synthase kinase 3, and protein phosphatase 1 to quality-control glycogen synthesis, ensure that glycogen is properly formed, and prevent further polyglucosan formation, Lafora bodies and Lafora disease.