Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA)

TLDR

Lafora disease diagnosis by skin biopsy can produce false positives and negatives, and although biopsies of other organs are more invasive, genetic testing may be inconclusive in certain mutation patterns. The study sought to identify hidden mutations and clarify genotypes to confirm Lafora disease in patients with apparently nonrecessive inheritance. The authors used single‑nucleotide polymorphism genotyping, quantitative PCR, and fluorescent in situ hybridization to detect mutations. They identified large EPM2A and EPM2B deletions undetectable by PCR, described simple routine detection methods, reported coding‑sequence changes of uncertain pathogenicity, confirmed adult‑onset Lafora disease is caused by EPM2B mutations, and noted major intrafamilial heterogeneity in age at onset.

Abstract

Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous <i>EPM2A</i> mutation and patients with apparently homozygous <i>EPM2B</i> mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large <i>EPM2A</i> and <i>EPM2B</i> deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to <i>EPM2B</i> mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.