Clinical Information

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the subsequent deposition of glycosylsphingolipids in tissues throughout the body, in particular in the kidney, heart, and brain. Variants within the GLA gene cause Fabry disease and more than 630 genetic alterations have been identified. Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic form of Fabry disease occurs in male patients who have less than 1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal opacity, and proteinuria. In addition, progressive kidney involvement leading to end-stage kidney disease (ESRD) typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The estimated incidence varies from 1 in 3000 infants detected via newborn screening to 1 in 10,000 male patients diagnosed after onset of symptoms.

Male patients with residual alpha-Gal A activity greater than 1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in life: a kidney variant associated with ESRD but without the pain or skin lesions; a cardiac variant typically presenting in the 6th to 8th decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; and a cerebrovascular variant presenting as stroke or transient ischemic attack. The variant forms of Fabry disease may be underdiagnosed.

Female patients who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected. Measurement of alpha-Gal A activity is not generally useful for identifying carriers of Fabry disease, as many of these individuals will have normal levels. Therefore, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis, Varies) is recommended to detect carriers.

Unless irreversible damage has already occurred, treatment with enzyme replacement therapy has led to significant clinical improvement in affected individuals. In addition, some adult patients may be candidates for an oral chaperone therapy. For this reason, early diagnosis and treatment are desirable and, in a few US states, early detection of Fabry disease through newborn screening has been implemented.

Absent or reduced alpha-Gal A in blood spots (AGABS / Alpha-Galactosidase, Blood Spot), leukocytes (this test), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. The biomarkers globotriaosylsphingosine (LGBWB / Globotriaosylsphingosine, Blood) and ceramide trihexosides (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine) may be elevated in patients with Fabry disease and may aid in the diagnostic evaluation of female patients. Molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis, Varies) allows for detection of the disease-causing variant in both male and female patients.