EPM2A – Lafora Disease

Lafora disease is a progressive, fatal form of autosomal recessive myoclonic epilepsy characterized by adolescent-onset seizures, action myoclonus, cognitive decline, and accumulation of polyglucosan inclusions (Lafora bodies) in neurons. The EPM2A gene (HGNC:3413), encoding the dual-specificity phosphatase laforin, was identified by positional cloning on chromosome 6q24, with biallelic mutations co-segregating in at least nine unrelated families and nine affected relatives (PMID:9771710).

Extensive mutational screening across multiple cohorts has revealed over 114 distinct pathogenic EPM2A variants—including missense, nonsense, splice-site, and small deletions—with truncating mutations accounting for roughly 60% of alleles. The recurrent c.721C>T (p.Arg241Ter) variant alone is found in ~40% of patients in certain populations (PMID:11175283). In total, more than 250 genetically confirmed Lafora cases have been described, supporting a definitive gene–disease relationship (PMID:19267391).

Inheritance is strictly autosomal recessive, with affected individuals harboring biallelic EPM2A mutations. Segregation analysis in multiple consanguineous pedigrees confirms complete penetrance of pathogenic alleles. One exemplar variant, c.721C>T (p.Arg241Ter), has been repeatedly observed in homozygous or compound heterozygous states in classic Lafora presentations.

Functional studies demonstrate that laforin forms a complex with the E3-ubiquitin ligase malin, regulating glycogen metabolism and preventing polyglucosan accumulation. Epm2a–/– mouse models develop neurodegeneration, Lafora bodies, ataxia, and spontaneous myoclonus, mirroring the human disease phenotype (PMID:12019206). In cellular systems, laforin deficiency or silencing leads to impaired proteasomal function, increased endoplasmic reticulum stress, and apoptosis in neuronal cells (PMID:19529779).

Although EPM2A mutations account for the majority of Lafora cases, a subset of families lacking EPM2A or NHLRC1 mutations suggests additional genetic heterogeneity and potential loci (PMID:15304597).

Integration of genetic and experimental data supports a definitive ClinGen classification for EPM2A–Lafora disease. Biallelic loss-of-function variants in EPM2A lead to laforin deficiency, aberrant glycogen phosphorylation, and neurodegeneration. Genetic testing of EPM2A is critical for diagnosis and family planning, while emerging therapies targeting glycogen metabolism hold promise.

Key Take-home: Biallelic EPM2A mutations definitively cause autosomal recessive Lafora disease, underpinning the clinical utility of targeted genetic testing for diagnosis and counseling.

References

• Nature Genetics • 1998 • Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy PMID:9771710
• European Journal of Human Genetics • 2000 • Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions PMID:11175283
• Human Mutation • 2009 • Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes PMID:19267391
• Human Molecular Genetics • 2002 • Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice PMID:12019206
• PLoS One • 2009 • Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin PMID:19529779
• Neurology • 2004 • Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus PMID:15304597

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