Abstract
Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD.
Highlights
Lafora disease (LD) is an autosomal recessively inherited disease that results from mutations in either the gene encoding for laforin (EPM2A) [1,2] or malin (EPM2B, called NHLRC1) [3]
LD as as indicated indicated by by the Mutations leading to non-functional laforin or malin result leading to non-functional laforin or malin result in in formation formation and and accumulation accumulation of of Lafora
Important questions are (1) how the absence of laforin or malin inflicts these changes in glycogen structure, and (2) whether these changes contribute to glycogen insolubility, Lafora bodies (LBs) accumulation, and LD
Summary
Lafora disease (LD) is an autosomal recessively inherited disease that results from mutations in either the gene encoding for laforin (EPM2A) [1,2] or malin (EPM2B, called NHLRC1) [3]. Patients enduring in a Some vegetative state and succumbing to the disease, usually withinare tenbedridden, years of symptom onset. EPM2A or EPM2B, describing from patients a later onsetprogression or differentin rate of progression, e.g., a in slower progression in describing patientswith withEPM2B a later mutations onset or different particular patients [8,9,10,11]. A hallmark of LDliver, is theand accumulation of Lafora (LBs) in various tissues, including skin, skeletal muscle, heart, brain. LBs are stainedbodies on tissue sections with Schiff reagent following skeletal muscle, heart, liver, brain. Understanding of the mechanisms underlying the underlying the pathogenesis of LD is paramount for the development of appropriate treatment pathogenesis of LD strategies
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