Abstract

Background: Lafora’s progressive myoclonic epilepsy (Lafora’s disease) is an autosomal recessive neurodegenerative disorder characterised by the presence of polyglucosan intracellular inclusions called Lafora bodies. Mutations in two genes, EPM2A and NHLRC1, have been shown to cause the disease. A previous study showed mutations in the EPM2A gene in 14 Lafora’s disease families and excluded the involvement of this gene in five other families who were biopsy proven to have the disease.

Objective: To relate the genetic findings to the clinical course of the disease.

Methods: As part of an ongoing mutational study of the Lafora’s disease genes, five new families with the disease were recruited and the genetic analysis was extended to screen the entire coding region of the NHLRC1 gene. Genotype–phenotype correlations were carried out.

Results: Seven NHLRC1 mutations were identified, including five novel mutations (E91K, D195N, P218S, F216_D233del, and V359fs32), in eight families with Lafora’s disease. On relating the genetic findings to the clinical course of the disease it was shown that patients with NHLRC1 mutations had a slower rate of disease progression (p<0.0001) and thus appeared to live longer than those with EPM2A mutations. A simple DNA based test is described to detect the missense mutation C26S (c.76T→A) in the NHLRC1 gene, which is prevalent among French Canadians.

Conclusions: Patients with NHLRC1 mutations have a slower rate of disease progression than those with EPM2A mutations.