Abstract
Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD.
Highlights
Lafora disease (LD, OMIM254780, ORPHA501) is a rare and fatal form of progressive myoclonus epilepsy (PME)
It is assumed either that the mutation present in EPM2A or in EPM2B only partially affects the function of the corresponding protein, or that the presence of genetic or environmental modifiers influences the regular progression of the disease [13,14,15,16]
Malin is encoded by the single exon EPM2B gene, located on chromosome 6q22.3 of the human genome, which produces a major mRNA with an ORF of 1185 nts, according to the ENSEMBL
Summary
Lafora disease (LD, OMIM254780, ORPHA501) is a rare and fatal form of progressive myoclonus epilepsy (PME). The term PME comprises a group of neurological disorders characterized by the presence of focal and generalized seizures, myoclonus and progressive neurodegeneration, accompanied with cerebellar signs and dementia [1,2,3]. LD patients enter in a vegetative state with continuous myoclonus, requiring tube feeding and artificial respiration. They die, usually within the first decade from onset of the first symptoms, from status epilepticus or aspiration pneumonia [6,7]. We discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD
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