Epm2bP71A and Epm2bD148N knock-in mouse models of Lafora disease exhibit distinct and pronounced neurological alterations.

Lafora disease is a rare, autosomal recessive neurodegenerative disorder characterized by the progressive accumulation of abnormal, insoluble, and hyperphosphorylated forms of glycogen, known as Lafora bodies, in the brain and other tissues. The disease typically manifests during early adolescence with myoclonus, seizures, and rapidly progressive cognitive decline, ultimately leading to severe neurological deterioration and death within a decade of onset. Mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin-key regulators of glycogen metabolism-are the underlying cause of Lafora disease. Current research focuses on understanding the molecular mechanisms of the disease and exploring potential therapeutic approaches, including gene therapy, antisense oligonucleotides, enzyme-based therapies, and pharmacological interventions aimed at mitigating glycogen accumulation and alleviating disease symptoms. Multiple mouse models have been generated to advance our understanding of disease pathogenesis and facilitate treatment development. These include models deficient in Epm2a or Epm2b gene expression, the Epm2a-/- and Epm2b-/- mouse models, and a knock-in mouse model harboring the most frequent mutation in the Epm2a gene, the R240X mutation. Recently, we developed two new knock-in mouse models with Epm2b gene mutations. In this work, we describe the generation and characterization of these malin knock-in mice and compare their phenotype with Epm2b-/- mice. These new models exhibit distinct neurological alterations, including motor and cognitive impairments, epileptic-like activity and altered synaptic plasticity. Based on these results, they can serve as valuable models for studying specific aspects of Lafora disease, providing more suitable tools for future research.