Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers.

Anderson-Fabry disease (E C 3.2.1.22, MIM 301500) is an X linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (GLA). 2 The onset of the disease and the severity of clinical manifestations depend principally on residual GLA enzymatic activity. Fabry disease can be classified into two clinical phenotypes: the classical form and the cardiac variant. 3 The classical form is mainly characterised, in affected hemizygous males, by angiokeratoma, acroparaesthesias, hypohidrosis, pains, fever crises, and involvement of the kidneys, brain, and heart. Neurological and/or psychological manifestations with personality disturbances can also occur. The cardiac variant is characterised by symptoms restricted to cardiac abnormalities, including conduction defects and/or late onset cardiomyopathy with left ventricular hypertrophy. 3 4 A prevalence of Fabry disease in a referral population of male patients with a clinical diagnosis of late onset hypertrophic cardiomyopathy (HCM) has also been reported. The X linked disorders affect males, while the female carriers are generally asymptomatic, owing in part to the random inactivation of the X chromosome. Fabry female carriers can be asymptomatic or clinically affected, usually with a late onset and mild form of the disease. Corneal abnormalities are the most frequent clinical manifestations. The human GLA gene, mapped on Xq22, is organised in seven exons encompassing over 12 kb. So far, about 265 mutations spread throughout the GLA gene in all exons have been reported in the Human Gene Mutation Database Web site and, in addition, a further 65 have been published. 9 Recently, Garman and Garboczi constructed a model of the human GLA enzyme, based on the x ray structure of the closely related enzyme alpha-N-acetylgalactosaminidase (alphaNAGAL), in which they mapped more than 190 reported point and stop mutations. They identified two types of GLA gene mutations: one disrupts the active site of the enzyme and the other affects the stability of folded protein. The diagnosis of Fabry disease in male patients can be easily made through enzymatic GLA assay in plasma, leucocytes, or cultured fibroblasts but it is very difficult to determine the carrier status in females. Because of X chromosome inactivation even obligate heterozygous females can show normal GLA enzymatic activity. The only certain method of detecting a female carrier is through molecular analysis. Fabry, Hunter, and Danon disease are the only X linked lysosomal storage diseases. Most of the Fabry carrier females are symptomatic while the Hunter carrier females, with a normal karyotype, do not usually show clinical manifestations. Twins heterozygous for the GLA enzymatic defect showing discordant phenotypic expression have been reported. Random X inactivation has been reported for the GLA gene. X inactivation studies in two carrier female monozygotic twins showing a discordant expression of the same mutation of the GLA gene have been described. So far, no further studies on X inactivation have been carried out on manifesting Fabry female carriers. GLA enzyme replacement therapy is now available to treat Fabry patients. 15 With the aim of genotype/phenotype correlation and in order to develop better patient care and therapeutic management, molecular studies were carried out on 18 Italian patients affected by Fabry disease in 14 unrelated families and in their relatives. In order to determine a correlation between clinical manifestations in Fabry carriers, X inactivation studies on four carrier females from the same family are reported.