Anderson-Fabry disease

Abstract

The diagnosis of Anderson-Fabry disease in a male patient who has a negative or unknown family history requires a knowledge of this disorder's pleiotropic clinical manifestations and a high index of suspicion in young men with acroparesthesias, petechiae, heat intolerance, unexplained hyperpyrexia, or proteinuria. The ophthalmologist will establish the clinical diagnosis occasionally on the basis of a routine slit-lamp examination. More often than is necessary or appropriate, Anderson-Fabry disease is first suggested by the renal pathologist after a biopsy exploring the cause of proteinuria, abnormal sediment, or azotemia. What is true for hemizygotes holds for heterozygous women as well, although clinicians are even less likely to think of Fabry disease in a woman in her fifth or sixth decade who has renal disease or heat intolerance. Here the ophthalmologist can be particularly valuable in quickly spotting the typical corneal opacities. Regardless of the level of assurity of the clinical diagnosis, all patients, men and women, should have an assay of α-galactosidase A activity performed, using plasma, leukocytes or cultured skin fibroblasts as a source. Hemizygotes can be unequivocally diagnosed in this way. There is some overlap of the range of enzyme activity in heterozygotes with the low-activity tail of unaffected controls, so that study of multiple enzymes and family members or cloning of skin fibroblasts searching for two lines, one deficient and one normal, will be necessary in about 10-15% of women in order to establish carrier status. Plasma or cells can be assayed for GSL content in order to establish reliably the diagnosis in hemizygotes and in many heterozygotes. The assay involves laborious steps and high-performance liquid chromatography; while the methods continue to improve, enzyme assay remains the biochemical test of choice. Prenatal diagnosis of the affected male fetus can be offered to known heterozygotes desirous of having their own children. The diagnosis can be established by assaying cultured amniocytes for α-galactosidase A activity; the family can then choose whether to abort an affected fetus.