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 glycosphingolipids in tissues throughout the body; in particular, in the kidney, heart, and brain. Disease-causing variants within the GLA gene cause Fabry disease. 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 renal involvement leading to kidney failure typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease.

Male patients with residual alpha-Gal A activity greater than 1% are at risk for a late-onset form of Fabry disease. Clinical manifestations may include adult-onset cardiac disease with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; kidney failure without skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack. The variant forms of Fabry disease may be underdiagnosed.

Female patients with Fabry disease can have clinical presentations ranging from asymptomatic to severely affected. Measurement of alpha-Gal A activity is not generally useful for identifying female individuals with Fabry disease, as many of them will have normal levels. Therefore, molecular genetic analysis of the GLA gene (GLA / Fabry Disease, GLA Gene Sequencing with Deletion/Duplication, Varies) is recommended.

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 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 (PLSD / Lysosomal and Peroxisomal Disorders Screen, Blood Spot), leukocytes (AGAW / Alpha-Galactosidase, Leukocytes), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. Molecular sequence analysis of the GLA gene (GLA / Fabry Disease, GLA Gene Sequencing with Deletion/Duplication, Varies) allows for detection of the disease-causing variant in both male and female patients. The biomarkers globotriaosylsphingosine (LGB3S / Globotriosylsphingosine, Serum) and ceremide trihexosides (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine) are typically elevated in symptomatic patients with Fabry disease and may aid in the diagnostic evaluation of female patients and individuals with a variant of uncertain significance in GLA.

For more information see Fabry Disease Testing Algorithm and Fabry Disease: Newborn Screen-Positive Follow-up