Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review

The lysosomal disorders (LD) are a heterogeneous group of approximately 50 disorders [1,2] with prevalence around 1:5,000 to 1:7,000 in live births [3,4]. Among other mechanisms involved in the degradation of macromolecules in lysosomes, the disease may be due to the deficiency of a specific hydrolase, a defect on the post-translational processing of the enzyme, or a transport defect across the lysosomal membrane [2,5]. The deficiency of a single enzyme or protein causes the blockage of an entire pathway making the substrate inaccessible to further hydrolysis by other lysosomal enzymes. It is important to stress that the gene products involved in the LD usually are not cell autonomous, as they could be secreted and uptaken on cells which do not produce them. Furthermore, in most LD more than one compound is accumulated, as in Mucopolysaccharidosis II (MPS II or Hunter syndrome), in which the main storage materials are dermatan sulphate and heparan sulphate; however, other substrates like ganglioside GM2 and GM3 and subunit c of mitochondrial ATP synthase are also accumulated in the brain [6]. The new concepts in cell biology led to the proposal of a new classification of LSD by Platt and Walkley [2] (Table 1).Among the over 300 human X-linked diseases described so far, only three are LD: Fabry disease (MIM 301500), MPSII II (MIM 30900), and Danon disease (MIM 300257). This review will focus on the clinical heterogeneity found among heterozygotes of the two most frequent conditions: Fabry disease and MPS II.Fabry disease is a rare X-linked lysosomal inborn error of glycosphingolipid catabolism which results from the deficient activity of lysosmal hidrolase α galactosidase A (α-GAL; EC 3.2.1.22). The estimated incidence of this rare disease is 1:40,000-117,000 live male births [4,7,8]. This figure, however, may be underestimated, as screening performed in newborn males in a Northwestern Italian region showed an incidence of 1 in ~4,000 males [9]. The α-galactosidase g