G.P.15.09 Unexpected high percentage of asymptomatic subjects carrying the FSHD molecular defect: Which factors contribute to the disease mechanism?

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy characterized by selective involvement of muscle groups and wide variability in clinical spectrum. Penetrance is considered complete by the age of 50. The FSHD molecular defect consists in reduced number of a 3.3 kb repeat (D4Z4) tandemly arrayed on chromosome 4q. The presence of EcoRI alleles shorter that 38 kb is considered diagnostic for the disease. However since molecular analysis has become a widely used tool for FSHD diagnosis, several observations have emerged to complicate the evaluation of FSHD patients and therefore prognosis. To obtain information that can define the natural history of the disease and eventually generate prognostic tools, we collected clinical and molecular data from a large, molecularly defined cohort of FSHD subjects. The clinical severity of the disease was numerically defined by using a clinical evaluation scale specifically designed. The FSHD score, which may range from 0 (no signs) to 15 (wheelchair bound), was generated through the functional evaluation of six muscle groups affected in FSHD (available at www.fshd.it). 350 subjects carrying D4Z4 deleted alleles and belonging to FSHD families were examined. Our analysis revealed that over 30% of these subjects carrying D4Z4 deletion are asymptomatic (FSHD score 0–1). Notably, the percentage of asymptomatic carriers is 38% in carriers of age ranging between 41–50 years and is still 22% within the group of carriers of 61–71 years of age. Interestingly, in families in which two deleted alleles segregate the percentage of asymptomatic subjects increases to 44%. These findings indicate that D4Z4 deletion is necessary but not sufficient to cause the disease and emphasize the complexity of the mechanisms underlying FSHD pathophysiology. Identification and definition of the weight of additional factors in the development of FSHD will lay the basis for a more precise prognosis and future therapeutic intervention.