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Lafora disease — from pathogenesis to treatment strategies

Nature Reviews Neurology volume 14, pages 606–617 (2018)Cite this article

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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.

Key points

  • Lafora disease, a lethal, autosomal recessive, progressive myoclonus epilepsy, is caused by loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively.

  • A large variety of pathogenic variants in EPM2A and NHLRC1 exists, with even distribution across both genes; variants include missense, nonsense and frameshift mutations, as well as larger deletions.

  • Laforin and malin are implicated in glycogen metabolism and are presented as part of a glycogen quality control mechanism, which decreases the risk of precipitation of individual glycogen molecules.

  • In the absence of a functional laforin–malin complex, structurally abnormal glycogen becomes insoluble and accumulates as Lafora bodies, which drive disease progression in the brain.

  • The lack of curative treatments and the current understanding of pathogenesis are driving investigations into a variety of therapeutic strategies for Lafora disease, including reduction in brain glycogen synthesis and replacement of the non-functional gene.

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Fig. 1: Causative mutations in Lafora disease.
Fig. 2: Impaired glycogen metabolism in Lafora disease.
Fig. 3: Mechanistic model for Lafora body formation and accumulation.
Fig. 4: Diagnosis of Lafora disease.
Fig. 5: Overview of therapeutic strategies in Lafora disease.

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Acknowledgements

The authors’ research work, some of which is described in this Review, is funded by families and friends of the Chelsea’s Hope Lafora Disease Research Fund, Associazione Italiana Lafora (AILA), France-Lafora, the Milana and Tatjana Gajic Lafora Disease Foundation, Genome Canada, the Ontario Brain Institute and the National Institute of Neurological Disorders and Stroke of the NIH under award number P01 NS097197. B.A.M. holds the University of Texas Southwestern Jimmy Elizabeth Westcott Chair in Pediatric Neurology. The authors thank S. Arnold (University of Texas Southwestern) for providing images of EEG and skin biopsy material from a patient with Lafora disease. This Review is dedicated to the memory of Adela Richer, a patient with Lafora disease who inspired this work and sadly passed away as the article was being completed.

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Nature Reviews Neurology thanks J. Guinovart and the other anonymous reviewers for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

    Felix Nitschke, Saija J. Ahonen, Silvia Nitschke & Berge A. Minassian

  2. Division of Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA

    Sharmistha Mitra & Berge A. Minassian

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Contributions

F.N., S.J.A., S.N. and S.M. researched data for the article. F.N., S.N. and B.A.M. made substantial contributions to discussions of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Berge A. Minassian.

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Related links

The Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database: http://projects.tcag.ca/lafora/

OMIM 254780: https://www.omim.org/entry/254780?search=254780&highlight=254780

OMIM 611556: https://www.omim.org/entry/611556?search=611556&highlight=611556

OMIM 613507: https://www.omim.org/entry/613507?search=613507&highlight=613507

Online Mendelian Inheritance in Man: https://www.omim.org/

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Nitschke, F., Ahonen, S.J., Nitschke, S. et al. Lafora disease — from pathogenesis to treatment strategies. Nat Rev Neurol 14, 606–617 (2018). https://doi.org/10.1038/s41582-018-0057-0

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