From the Guidelines
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene, leading to deficiency of the enzyme alpha-galactosidase A, resulting in accumulation of glycosphingolipids in various tissues and organs throughout the body. This condition is X-linked, primarily affecting males, though females can experience symptoms of varying severity 1. Symptoms typically begin in childhood or adolescence and include:
- Burning pain in hands and feet
- Decreased ability to sweat
- Dark red spots on the skin (angiokeratomas)
- Corneal clouding
- Gastrointestinal issues
- Progressive damage to the heart, kidneys, and brain
Treatment involves enzyme replacement therapy with medications like agalsidase beta or agalsidase alfa, administered intravenously every two weeks, as emphasized in the study published in the Annals of Internal Medicine 1. Management also includes symptom-specific treatments such as pain medications, antihypertensives for kidney protection, and anticoagulants for stroke prevention. Early diagnosis and treatment are crucial to prevent irreversible organ damage, so genetic testing is recommended for family members of affected individuals. Multidisciplinary care involving cardiologists, nephrologists, neurologists, and genetic counselors is essential for optimal management of this complex, progressive condition. Enrollment of all patients in a Fabry disease registry is encouraged to increase knowledge of the natural history and complications of the disease and the efficacy of treatment regimens 1.
From the FDA Drug Label
Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease.
Fabry disease is a condition characterized by a deficiency of the alpha-galactosidase A (alpha-Gal A) protein, leading to the accumulation of glycosphingolipids such as globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3) 2.
From the Research
Definition and Characteristics of Fabry Disease
- Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency of α-galactosidase A (AGAL) due to mutations in the α-galactosidase A gene (GLA) 3, 4, 5, 6, 7.
- The disease is characterized by the accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), leading to a multisystemic disease with progressive renal failure, cardiomyopathy, and strokes 3, 4, 5, 6, 7.
Diagnostic Confirmation
- Diagnostic confirmation in male patients is based on the detection of AGAL deficiency in blood leukocytes 3.
- In women, molecular genetic detection of a causal mutation is required due to potentially high residual enzymatic activity 3.
Treatment Options
- Current treatment options for FD include recombinant enzyme replacement therapy (ERT) with intravenous agalsidase-alfa or agalsidase-beta, and oral chaperone therapy with migalastat 3, 4, 6, 7.
- ERT enables cellular Gb3 clearance and improves the burden of disease, but can lead to infusion-associated reactions and the formation of neutralizing antidrug antibodies in some patients 3.
- Chaperone therapy with migalastat is an oral treatment that stabilizes specific mutant forms of α-Gal, defined as "amenable" to migalastat, and has shown safety and efficacy in improving symptoms and disease progression 6, 7.