Fabry disease

Fabry disease, also known as X‑linked sphingolipidosis (Anderson–Fabry disease, angiokeratoma corporis diffusum, alpha‑galactosidase A deficiency), belongs to the group of rare genetic disorders. It is a lysosomal metabolic disorder with an estimated incidence of approximately 1:40,000. It is an X‑linked inherited disease caused by deficiency of the lysosomal enzyme alpha‑galactosidase A (α‑GAL). Patients with this disease are unable to properly degrade and metabolize certain substances—specifically glycosphingolipids, which are normally derived from dietary fats. Reduced or absent activity of α‑GAL leads to accumulation of globotriaosylceramide (Gb3 / GL‑3) deposits in the endothelium (vascular lining) and visceral tissues. GL‑3 accumulates in the walls of blood vessels and in various organs—especially the heart, kidneys, and central nervous system—causing progressive morphological and functional damage and resulting in multisystem organ involvement.

The disease was first described in 1898 by the English physician William Anderson and the German physician Johann Fabry as angiokeratoma corporis diffusum universale, also known as Fabry disease or Anderson–Fabry disease.

Symptoms

Clinical manifestations are difficult to predict. Symptoms usually begin in childhood or adolescence with mild manifestations such as episodic pain in the fingers and hands, reduced sweating (hypohidrosis), and cutaneous angiokeratomas, followed by gradual renal and cardiac involvement, including concentric myocardial hypertrophy complicated by arrhythmias.

Diagnosis

The cornerstone of diagnosis is genetic and molecular testing, optionally supplemented by organ biopsy (not routinely performed), along with confirmation of cardiomyopathy and renal disease. Based on structural cardiac or renal changes, cardiologists or nephrologists may refer patient samples for genetic testing. Once the diagnosis is confirmed, genetic testing of family members is recommended.

Treatment

Without treatment, patients typically die during the fourth to fifth decade of life. The foundation of therapy is enzyme replacement therapy (ERT) with intravenous agalsidase to replace the deficient enzyme. This therapy is provided in specialized metabolic centers.

Additional management includes treatment of associated complications and symptomatic therapy:

• nephroprotective therapy,
• analgesic treatment for pain and acroparesthesia,
• management of gastrointestinal symptoms, including pancreatic enzyme substitution and dietary modification,
• treatment of heart failure and cardioprotective therapy,
• and management of cardiac arrhythmias, which are common (including possible implantation of a pacemaker or implantable cardioverter‑defibrillator).

• initially typical acroparesthesia – recurrent attacks of severe pain in the limbs
• pain triggered by physical exertion or temperature changes
• pain episodes lasting hours to days
• episodes of fever
• intolerance to heat, cold, and exercise
• reduced sweating
• corneal dystrophy
• in 80% of patients, characteristic skin lesions – angiokeratomas
• angiokeratomas mainly present on the lower abdomen and buttocks
• proteinuria (elevated protein levels in urine), microscopic hematuria
• progressive renal involvement leading to renal failure
• left ventricular enlargement (concentric hypertrophic cardiomyopathy)
• heart valve involvement
• disorders of the cardiac conduction system
• cardiac rhythm disturbances, arrhythmias
• development of congestive heart failure or myocardial infarction
• possible occurrence of early‑onset stroke
• dizziness
• hearing loss and balance impairment