Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA 
gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a 
heterogeneous spectrum of clinical manifestations that are caused by the 
deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for 
diagnosis in males, enzyme activity is not a reliable biochemical marker in 
heterozygous females due to random X-chromosome inactivation, thus rendering DNA 
sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most 
reliable test for the confirmation of diagnosis in females. The spectrum of GLA 
mutations is highly heterogeneous. Many polymorphic GLA variants have been 
described, but it is unclear if haplotypes formed by combinations of such 
variants correlate with FD, thus complicating molecular diagnosis in females 
with normal α-Gal-A activity. We tested 67 female probands with clinical 
manifestations that may be associated with FD and 110 control males with normal 
α-Gal-A activity. Five different combinations of GLA polymorphic variants were 
identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, 
p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not 
been reported so far, and both mutant forms were found to be responsive to the 
pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat 
hydrochloride). Analysis of the male control population, as well as male 
relatives of a suspected FD female proband, permitted the identification of 
seven different GLA gene haplotypes in strong linkage disequilibrium. The 
identification of haplotypes in control males provides evidence against their 
involvement in the development of FD phenotypic manifestations.