Abstracts

Rationale: Lafora disease is a fatal form of progressive myoclonus epilepsy characterized by the presence of intracellular glycogen-like inclusions. Symptoms start in childhood or adolescence usually with seizures and is followed by rapid and progressive cognitive and motor impairment. Most patients die within a decade of first symptoms. The disease is inherited following an autosomal recessive pattern and in more than 95% of the patients mutations in EPM2A or EPM2B are found. Methods: We reviewed clinical and genetic information from 104 Lafora disease patients studied in our center between 1996 and 2005, including patients from 26 previously unreported. Genetic analysis was performed by sequencing of the EPM2A and/or EPM2B genes. Results: One hundred four patients from 82 families were included in the study. Age at onset ranged from 4 to 22 years (mean=12.75 3.5). The most common initial symptom was a generalized tonic-clonic seizure (45%), followed by simple partial occipital seizures (16%), myoclonic seizures (15%) and absences (11%). Photosensitivity was present in 27 out of 36 patients. Cognitive deterioration occurred from 11 to 28 years (15.2 2.47), onset of gait disturbance from 13 to 30 years (16.2 2.8) and inability to walk alone from 13 to 23 years (18.1 2.06). Age at death ranged from 16 to 35 years but 60% of the patients died between 18 and 21 years. Progression of the disease (from first symptom to death) ranged from 4 to 28 years although for 65% of the patients an evolution of 5-9 years was observed. Three patients survived into the fourth decade of life. Fifty-seven families (70%) had mutations in EPM2A, 23 families (28%) in EPM2B and in 2 families (2.4%) no mutations were found in any of these genes. R241X was the most common mutation in EPM2A and P69A in EPM2B. Skin biopsies did not reveal any abnormalities in three individuals (two with mutations in EPM2A and one with a mutation in EPM2B). Genotype-phenotype correlations confirmed a milder course of the disease in patients with EPM2B mutations (p=0.034). A significant higher prevalence of simple partial occipital seizures was found in patients with mutations in EPM2A (p=0.021). When patients harboring a homozygous R241X mutation (21 individuals from 15 families) and those with heterozygous R241X mutations (13 individuals from 8 families) were compared, a significant longer progression of the disease (p=0.021) and an older age at which patients died (p=0.014) were found. Conclusions: The majority of patients with Lafora disease present a fairly homogeneous phenotype although there is wide variability regarding age at onset and patient survival, most patients dying at or before age 21 but with exceptionally high survivals in a few patients. Genetic or environmental factors yet to be discovered may condition a very long progression of the disease. Around 98% of our patients harbor mutations in EPM2A or EPM2B. Patients with EPM2B mutations seem to have a milder course of the disease.