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Genetics of Lafora progressive myoclonic epilepsy: current perspectives

Authors Kecmanovic M, Keckarevic-Markovic M, Keckarevic D, Stevanovic G, Jovic N, Romac S

Received 17 August 2015

Accepted for publication 22 January 2016

Published 2 May 2016 Volume 2016:9 Pages 49—53


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Martin H. Maurer

Miljana Kecmanović,1 Milica Keckarević-Marković,1 Dušan Keckarević,1 Galina Stevanović,2 Nebojša Jović,2 Stanka Romac,1,†

1Faculty of Biology, Center for Human Molecular Genetics, 2Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia

Stanka Romac passed away on December 13, 2015

Abstract: Lafora disease (LD) is a fatal neurodegenerative disorder caused by loss-of-function mutations in either laforin glycogen phosphatase gene (EPM2A) or malin E3 ubiquitin ligase gene (NHLRC1). LD is associated with gradual accumulation of Lafora bodies (LBs). LBs are aggregates of polyglucosan, a long, linear, poorly branched, hyperphosphorylated, insoluble form of glycogen. Loss-of-function mutations either in the EPM2A or in the NHLRC1 gene lead to polyglucosan formation. One hypothesis on LB formation is based on findings that laforin–malin complex downregulates glycogen synthase (GS) through malin-mediated ubiquitination, and the other one is based on findings that laforin dephosphorylates glycogen. According to the first hypothesis, polyglucosan formation is a result of increased GS activity, and according to the second, an increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan, while GS remains bound to the precipitating glycogen. In this review, we summarize all the recent findings that have important implications for the treatment of LD, all of them showing that partial inhibition of GS activity may be sufficient to prevent the progression of the disease. The current perspective in LD is high-throughput screening for small molecules that act on the disease pathway, that is, partial inhibitors of GS, which opens a therapeutic window for potential treatment of this fatal disease.

Keywords: Lafora disease, glycogen synthase, treatment

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