Lafora disease: Current biology and therapeutic approaches

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


The ubiquitin system impacts most cellular processes and is altered in numerous neurodegenerative diseases. However, little is known about its role in neurodegenerative diseases due to disturbances of glycogen metabolism such as Lafora disease (LD). In LD, insufficiently branched and long-chained glycogen forms and precipitates into insoluble polyglucosan bodies (Lafora bodies), which drive neuroinflammation, neurodegeneration and epilepsy. LD is caused by mutations in the gene encoding the glycogen phosphatase laforin or the gene coding for the laforin interacting partner ubiquitin E3 ligase malin. The role of the malin-laforin complex in regulating glycogen structure remains with full of gaps. In this review we bring together the disparate body of data on these two proteins and propose a mechanistic hypothesis of the disease in which malin-laforin's role to monitor and prevent over-elongation of glycogen branch chains, which drive glycogen molecules to precipitate and accumulate into Lafora bodies. We also review proposed connections between Lafora bodies and the ensuing neuroinflammation, neurodegeneration and intractable epilepsy. Finally, we review the exciting activities in developing therapies for Lafora disease based on replacing the missing genes, slowing the enzyme – glycogen synthase – that over-elongates glycogen branches, and introducing enzymes that can digest Lafora bodies. Much more work is needed to fill the gaps in glycogen metabolism in which laforin and malin operate. However, knowledge appears already adequate to advance disease course altering therapies for this catastrophic fatal disease.

Original languageEnglish (US)
JournalRevue Neurologique
StateAccepted/In press - 2021


  • E3 ubiquitin ligase
  • Gene therapy
  • Lafora disease
  • Laforin
  • Malin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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