Response [NEUROMUSCULAR DISORDERS]

This is a letter to the Editor in response to comments from Spatafora et al. Neuromuscul DisThe letter by Spadafora and coworkers questions the pathogenic role of heterozygous CAV3 T78M variant in a patient we recently described (Ricci et al, 2012) because the same heterozygous variant has been found in 3, out of 195, healthy unrelated controls. As an alternative hypothesis to explain our patient carrying both heterozygous D4Z4 reduction and CAV3 T78M variant the authors suggests that the dramatic reduction of caveolin-3 we observed in the muscle biopsy might be due to mutations in other genes. This interesting hypothesis is consistent with several reports suggesting that other genetic modifiers may be implied in Cav-3 deficiency, so that the same CAV3 mutation can lead to heterogeneous clinical phenotypes and muscle histopathological changes (REF). In particular the study by Traverso et al. (2008) suggested that the T78M mutation might results pathogenic only in homozygous feature through a loss-of-function mechanism. In our view the finding that CAV3 T78M mutation is a common variant with a frequency of 1.5% might disclose a different scenario. In fact by analyzing DNA elements at 4q35 in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients, we have recently discovered that 1.3 % of healthy unrelated subjects carry alleles of 21-35 kb in size on chromosome 4q associated with the 4APAS161 permissive haplotype (Scionti et al 2012). This discovery points at the possibility that in the heterozygous state D4Z4 reduction might produce a subclinical sensitized condition that requires other epigenetic mechanisms or a contributing factor to cause overt myopathy. In some rare cases, it could be by becoming homozygous (Scionti et al 2012b) while in others, it might be by the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports in which the FSHD contractions are found in association with a second molecular defect (REF). The clinical case, we have recently reported, seems to fall in this complex picture. The observation of Spatafora et al supports the idea that D4Z4 reduced allele as well CAV3 T78M variant, are not per se sufficient to cause a disease phenotype. In our patient, whose geographical origin is Calabria, the simultaneous mutations (heterozygous CAV3 T78M and 35 kb 4A161PAS D4Z4 allele) could play a synergistic effect in reaching disease threshold and determining overlapping phenotype.In light of this finding particular attention should be paid to the geographical origin of similar cases. As suggested by Spatafora et al, the frequency of the CAV3 T78M variant on the whole Italian territory should be established. In conclusion these population studies could have important relevance for prenatal genetic counseling of healthy carriers who are at risk of transmitting the mutation to next generation.