The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females

Abstract

We investigated 52 families of patients with facioscapulohumeral muscular dystrophy (FSHD1), including 172 patients (104 males and 68 females). Among 273 DNA samples which were analyzed with probe p13E-11, 131 (67 males and 64 females) were shown to carry an EcoRI fragment smaller than 35 kb; 114 among them were examined clinically and neurologically. Results of the present investigation showed that: a) there is no molecular evidence for autosomal or X-linked recessive inheritance of FSHD1; b) an excess of affected males, which is explained by a significantly greater proportion of females than males among asymptomatic cases and a significantly greater proportion of affected sons than daughters observed in the offspring of asymptomatic mothers; c) the penetrance of the FSHD1 gene until age 30 was estimated as 83% for both sexes but was significantly greater for males (95%) than for females (69%); d) new mutations occur significantly more frequently in females than males among somatic/germinal mosaic cases; and e) severely affected cases originated more often through new mutations or were transmitted through maternal than through paternal lines including somatic/germinal mothers. These observations have important implications for understanding the molecular mechanisms responsible for FSHD1 and for genetic and prognostic counseling according to the gender of the affected patient.

Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree

“…An excess of affected men has been reported for other autosomal Electronic letter dominant neurological disorders such as myotonic dystrophy, 32 33 Machado-Joseph disease or SCA3 cerebellar ataxia, 34 DRPLA, 35 and more recently facioscapulohumeral muscular dystrophy (FSHMD). 36 For SCA3, myotonic dystrophy, and DRPLA it has been suggested that the excess of affected males could be explained by meiotic drive favouring the transmission of enlarged alleles. However, in the case of FSHMD, DNA analysis showed that the proportion of men and women carrying the deleted abnormal EcoRI/BlnI allele was the same, thus suggesting other mechanisms to explain why women were less often or more mildly affected than men.…”

Facioscapulohumeral Dystrophy

“…This finding is particularly intriguing, as recent studies have demonstrated that the clinical expression of the disease may become more severe as the condition is passed from one generation to the next. 1,39,47,48 Despite the unequivocal association of the 4q35 short fragment with FSHD, the precise gene or genes affected by this defect have remained unknown. Despite an intensive search over the past 8 years, no genes have been identified in the 4q35 deleted region, a region that includes telomeric heterochromatin, which is usually not transcribed.…”

Equal proportions of affected cells in muscle and blood of a mosaic carrier of facioscapulohumeral muscular dystrophy

“…A relationship has been established between the severity of the disease and the percentage of peripheral blood lymphocytes (PBL) carrying the FSHD allele in combination with the residual repeat size . It has been reported, by these researchers and others, (Kohler et al 1996;Upadhyaya et al 1995;Zatz et al 1998) that a significant proportion of FSHD mosaic carriers are asymptomatic. However, it is not known if this occurs because the mosaicism is unequally distributed between different tissues and that in some cases, muscle is relatively spared for the presence of the disease allele or due to a mechanism that has not been identified yet.…”