Diagnosis and treatment of Fabry disease

Abstract

Fabry disease is caused by deficiency of a lysosomal enzyme, α–galactosidase, leading to accumulation of its substrate globotriosylceramide in various tissues such as vascular endothelial cells and ganglion cells. Due to the multiple organ involvement, various symptoms such as burning extremity pain, anhidrosis, skin lesion called angiokeratoma, renal failure, and heart failure develop progressively. In addition, one in five patients develop cerebrovascular disorder with the average onset of 40 years for males and 45 years for females. Fabry disease is therefore an important cause of juvenile cerebral infarction. Since the α–galactosidase A gene is on the long arm of the X chromosome, the genetic form is X–linked with men exhibiting severe symptoms as hemizygotes. However, 86% of heterozygous women also become symptomatic due to random X chromosome inactivation. Fabry disease can be ruled out for males with normal α–galactosidase activity in leukocytes, but not for females with the normal enzyme activity. Urine sediment analysis shows a grayish white or transparent spiral structure called mulberry body which may be helpful for the diagnosis of Fabry disease. As women develop left ventricular hypertrophy and cerebral infarction later than men but show cumulative incidence curve similar to men, enzyme replacement therapy should be started as soon as possible. The median age of the initial occurrence of the composite endpoint (kidney, heart, or stroke event, or death) can be delayed by about 10 years with enzyme replacement therapy. Therefore, the importance of early diagnosis of Fabry disease cannot be emphasized enough.