What is Fabry disease (Alpha-Galactosidase A deficiency)?

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, and treatment should ideally begin as soon as clinical signs and symptoms are observed, with enzyme replacement therapy being recommended for all patients with Fabry disease 1.

Overview of Fabry Disease

Fabry disease is an inborn error of metabolism with profound clinical consequences and a pathology that begins at birth, resulting in accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs throughout the body 1. The disease is X-linked, primarily affecting males, though females can experience symptoms of varying severity.

Symptoms and Treatment

Symptoms typically begin in childhood or adolescence and include burning pain in hands and feet, decreased sweating, gastrointestinal issues, skin rashes (angiokeratomas), corneal clouding, kidney dysfunction, heart problems, and stroke 1. Treatment centers on enzyme replacement therapy (ERT) with agalsidase alfa (Replagal) at 0.2 mg/kg or agalsidase beta (Fabrazyme) at 1.0 mg/kg, administered intravenously every two weeks. Newer oral therapy options include migalastat (Galafold), which works as a chaperone therapy for patients with amenable mutations, taken 123 mg every other day.

Management and Monitoring

Management requires a multidisciplinary approach with regular monitoring of kidney function, cardiac status, and neurological symptoms 1. Genetic counseling is important for affected families due to the hereditary nature of the condition. Control of hypertension is essential to minimize renal, cardiovascular, and cerebrovascular disease, and prophylaxis with antiplatelet or anticoagulant medication can be important for patients who have had transient ischemic attacks or a stroke 1.

Key Recommendations

• Enzyme replacement therapy should be initiated in all patients with Fabry disease as soon as clinical signs and symptoms are observed 1.
• Regular monitoring of kidney function, cardiac status, and neurological symptoms is crucial for effective management 1.
• Genetic counseling is important for affected families due to the hereditary nature of the condition 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. The enzyme α-galactosidase A catalyzes the hydrolysis of GL-3 and other α-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose Fabry disease is a condition caused by a deficiency of the alpha-galactosidase A (alpha-Gal A) enzyme, which is encoded by the GLA gene. This deficiency leads to the accumulation of certain lipids, such as globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3), in the body. The alpha-Gal A enzyme normally breaks down these lipids, but in Fabry disease, the enzyme is not functioning properly, resulting in their accumulation. 2 3

• Key points:
  • Fabry disease is caused by a deficiency of the alpha-Gal A enzyme
  • The alpha-Gal A enzyme is responsible for breaking down certain lipids, such as GL-3 and lyso-Gb3
  • In Fabry disease, these lipids accumulate in the body due to the enzyme deficiency
• Main idea: Fabry disease is a condition characterized by the deficiency of the alpha-Gal A enzyme, leading to the accumulation of certain lipids in the body.

From the Research

Definition and Cause of Fabry Disease

• Fabry disease is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations 4, 5, 6.
• The disease is caused by a deficiency of the enzyme alpha-galactosidase A, which leads to progressive, abnormal accumulation of neutral glycosphingolipids in the lysosome 6.
• Fabry disease is also known as Anderson-Fabry disease, and it is a rare inherited X-linked lysosomal storage disease 5, 6.

Symptoms and Progression of Fabry Disease

• The clinical onset of Fabry disease typically occurs during childhood or adolescence, with early symptoms of neuropathic pain, angiokeratomas, oedematous upper eyelids, peripheral vasospasm, and ophthalmological abnormalities 6.
• As the disease progresses through adulthood, several major organ systems may be affected, including cardiac disease, renal insufficiency, cerebrovascular attacks, and neurologic findings 6.
• Death usually occurs secondary to renal, cardiac, or cerebrovascular complications during the fourth or fifth decade of life 6.

Treatment Options for Fabry Disease

• Enzyme replacement therapy (ERT) is a major advance in the treatment of Fabry disease, with two formulations approved by the European Medical Evaluation Agency: agalsidase alpha and agalsidase beta 6.
• Agalsidase alpha is produced on the human fibroblast cell line, and agalsidase beta is produced from the Chinese hamster ovary cell line 6.
• Other treatment options include the chaperone migalastat, which was recently approved for Fabry disease patients with amenable GLA mutations 7.
• New therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy 7.