First, heterozygote detection by enzyme assay of carriers for this X-linked recessive disease is unreliable because obligate carriers can have normal activity due to random X-chromosomal inactivation. Mutation detection in Fabry disease is important for several reasons. Of note, non-coding sequence variants have been identified in О± -Gal A alleles from normal individuals and patients with Fabry disease (the SNP database), with the exception of D313Y, an exonic sequence variant that encodes an enzyme with 60-70 percent of wild-type activity, but does not cause disease in males or females with this variant. Most mutations have been private (ie unique to one or a few families), with the exception of certain mutations found in unrelated individuals that occurred at CpG dinucleotides, known hot spots for mutation.

To date, a variety of mutations have been identified which cause the classic phenotype, including missense, nonsense and splice-site mutations, as well as partial gene rearrangements, including small and large intragenic deletions and insertions (the Human Gene Mutation Database). These patients typically present with cardiac and/or renal disease and lack the major classical manifestations, including angiokeratoma, acroparesthesias, hypohidrosis and ocular abnormalities. In contrast to the classic phenotype, later-onset variants have been identified which have residual О±-Gal A activity. With advancing age, the progressive glycosphingolipid deposition, particularly in vascular endothelial lysosomes, leads to vascular disease of the heart, kidneys and brain, resulting in early demise, typically in the fourth or fifth decade of life. In classically affected males who have little, if any, О±-Gal A activity, onset of disease manifestations occurs in childhood or adolescence and is characterised by severe acroparesthesias, angiokeratoma, corneal and lenticular opacities and hypohidrosis. The enzymatic defect causes the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids with terminal О±-linked galactosyl moieties in the plasma and in tissue lysosomes throughout the body. These studies further define the molecular heterogeneity of the О±-Gal A mutations in classical Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and provide insights into the structural alterations of the mutant enzymes that cause the classic phenotype.ДЇabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, О±-galactosidase A (EC 3.2.1.22 О±-Gal A).

Of note, three novel mutations (approximately 10 per cent) were predicted not to significantly alter the glycoprotein's structure however, they were disease causing. Structural analyses based on the enzyme's three-dimensional structure predicted the effect of the 29 novel missense mutations on the mutant glycoprotein's structure. Transient expression of the individual mutations revealed that D264Y and Q312H were localised in the endoplasmic reticulum and had no detectable or markedly reduced activity, whereas V269M and A143T were localised in lysosomes and had approximately 10 per cent and approximately 35 per cent of expressed wild-type activity, respectively. In two classically affected families, affected males were identified with two mutations: one with two novel mutations, D264Y and V269M and the other with one novel (Q312H) and one previously reported (A143T) mutation. In 18 families, 17 previously reported mutations were identified, with R112C occurring in two families. The molecular lesions in the О±-Gal A gene causing the classic phenotype of Fabry disease in 66 unrelated families were determined.

Fabry disease, an X-linked recessive inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase, О±-galactosidase A (EC 3.2.1.22 О±-Gal A).

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