Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy

The gene for facioscapulohumeral muscular dystrophy (FSHD) has been mapped to chromosome 4q35. In most patients with FSHD, a deletion of 3.3 kb tandemly repeated units within the EcoRI fragment that can be detected by probe p13E-11 is associated with the disease. To elucidate the relation between the phenotype and the genotype in FSHD, we examined 91 Japanese unrelated families with a clinical diagnosis of FSHD (140 patients, 205 healthy individuals). Of these, 78 families (86%) had 4q35-FSHD (127 patients), in which 20 patients (20/127, 16%) were classified as early onset FSHD. We found that all nine patients with the smallest EcoRI fragments (10 to 11 kb) were classified among the early onset group (9/20, 45%), and these patients showed a high frequency of both epilepsy (4/9, 44%) and mental retardation (8/9, 89%). In contrast, none of the remaining patients with 4q35-FSHD had epilepsy or mental retardation. We conclude that FSHD patients with a large gene deletion in the FSHD gene region tend to have a higher chance of showing severe clinical phenotypes with CNS abnormalities. This finding may have practical implications for genetic counseling, although the molecular genetic background remains unclear.