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

Abstract

Most lysosomal diseases (LD) are inherited as autosomal recessive traits, but two important conditions have X-linked inheritance: Fabry disease and Mucopolysaccharidosis II (MPS II). These two diseases show a very different pattern regarding expression on heterozygotes, which does not seem to be explained by the X-inactivation mechanism only. While MPS II heterozygotes are asymptomatic in most instances, in Fabry disease most of female carriers show some disease manifestation, which is sometimes severe. It is known that there is a major difference among X-linked diseases depending on the cell autonomy of the gene product involved and, therefore, on the occurrence of cross-correction. Since lysosomal enzymes are usually secreted and uptaken by neighbor cells, the different findings between MPS II and Fabry disease heterozygotes can also be due to different efficiency of cross-correction (higher in MPS II and lower in Fabry disease). In this paper, we review these two X-linked LD in order to discuss the mechanisms that could explain the different rates of penetrance and expressivity observed in the heterozygotes; this could be helpful to better understand the expression of X-linked traits.

Figure 1

Male patient with Fabry disease (left, child) and a heterozygote for Fabry disease (right, mother). The male patient is 21 years old and presents pain in hands and achroparestesias, temperature intolerance, hypohidrosis, and proteinuria. He presents a 30delG in the α-GAL gene. The mother is 62 years old and has diabetes mellitus, cardiopathy and proteinuria. She is a carrier of 30delG in the α-GAL gene. Image use authorized by patients.

Figure 2

Male patient with MPS II (left, child) and a heterozygote for MPS II (left, mother). The patient is 10 years old and presents severe mental handicap, coarse face, hepatosplenomeagly, dysostosis multiplex, joint contractures, obstructive airway disease, mitral regurgitation, deafness, and hydrocephaly. He presents a total deletion of the IDS gene. The mother is a MPS II carrier and is asymptomatic. Image use authorized by patient.