Lafora disease - from pathogenesis to treatment strategies
- PMID: 30143794
- PMCID: PMC6317072
- DOI: 10.1038/s41582-018-0057-0
Lafora disease - from pathogenesis to treatment strategies
Abstract
Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. The disease usually manifests in previously healthy adolescents, and death commonly occurs within 10 years of symptom onset. Lafora disease is caused by loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The absence of either protein results in poorly branched, hyperphosphorylated glycogen, which precipitates, aggregates and accumulates into Lafora bodies. Evidence from Lafora disease genetic mouse models indicates that these intracellular inclusions are a principal driver of neurodegeneration and neurological disease. The integration of current knowledge on the function of laforin-malin as an interacting complex suggests that laforin recruits malin to parts of glycogen molecules where overly long glucose chains are forming, so as to counteract further chain extension. In the absence of either laforin or malin function, long glucose chains in specific glycogen molecules extrude water, form double helices and drive precipitation of those molecules, which over time accumulate into Lafora bodies. In this article, we review the genetic, clinical, pathological and molecular aspects of Lafora disease. We also discuss traditional antiseizure treatments for this condition, as well as exciting therapeutic advances based on the downregulation of brain glycogen synthesis and disease gene replacement.
Conflict of interest statement
Competing interests
The authors declare no competing interests.
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References
-
- Delgado-Escueta AV, Ganesh S & Yamakawa K Advances in the genetics of progressive myoclonus epilepsy. Am. J. Med. Genet. 106, 129–138 (2001). - PubMed
-
- Girard JM, Turnbull J, Ramachandran N & Minassian BA Progressive myoclonus epilepsy. Handb. Clin. Neurol. 113, 1731–1736 (2013). - PubMed
-
- Lafora GR & Glueck B Beitrag zur Histopathologie der myoklonischen Epilepsie [German]. Z. Gesamte Neurol. Psychiatr. 6, 1–14 (1911).
-
- Sakai M, Austin J, Witmer F & Trueb L Studies in myoclonus epilepsy (Lafora body form). II. Polyglucosans in systemic deposits of myoclonus epilepsy and in corpora amylacea. Neurology 20, 160–176 (1970). - PubMed
-
- Minassian BA et al. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat. Genet. 20, 171–174 (1998). - PubMed
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