What Is Fabry Disease and Who Does It Affect?

Fabry disease is a progressive, inherited disorder caused by mutations in the GLA gene, which leads to deficiency of an enzyme called alpha-galactosidase A. This enzyme deficiency causes a buildup of a fatty substance called globotriaosylceramide (Gb3) in cells throughout the body, particularly affecting the heart, kidneys, and nervous system.

As an X-linked disorder, Fabry disease primarily affects males, though females can experience symptoms of varying severity. The condition affects approximately 1 in 40,000 to 60,000 males worldwide, making it one of the more common lysosomal storage disorders, though it remains relatively rare in the general population. Symptoms typically begin in childhood or adolescence but can sometimes go undiagnosed until adulthood when more severe complications arise.

Early Warning Signs of Fabry Disease

The initial symptoms of Fabry disease often appear during childhood or adolescence. One of the most distinctive early signs is acroparesthesia—burning pain and tingling in the hands and feet that can become debilitating during periods known as "Fabry crises," often triggered by fever, exercise, stress, or weather changes.

Skin manifestations are another hallmark of early Fabry disease. Many patients develop angiokeratomas—small, dark red spots that typically appear on the lower abdomen, genital area, and inner thighs. Additionally, decreased or absent sweating (hypohidrosis or anhidrosis) is common, leading to heat and exercise intolerance.

Gastrointestinal issues frequently affect those with Fabry disease, including chronic abdominal pain, diarrhea, constipation, nausea, and vomiting. These symptoms can significantly impact quality of life and may be mistaken for other digestive disorders, potentially delaying diagnosis.

Advanced Symptoms and Organ Involvement

As Fabry disease progresses, more serious complications develop due to the accumulation of Gb3 in various organs. Kidney involvement is particularly concerning, with patients developing proteinuria (protein in urine) and progressive kidney function decline that may eventually lead to kidney failure requiring dialysis or transplantation.

Cardiac manifestations include left ventricular hypertrophy, arrhythmias, valve abnormalities, and coronary artery disease. These heart-related complications are a major cause of reduced life expectancy in untreated Fabry disease patients.

Neurological symptoms extend beyond pain to include hearing loss, tinnitus, vertigo, and a significantly increased risk of stroke, even in relatively young patients. Many individuals also develop corneal whorling (cornea verticillata)—a distinctive pattern in the cornea that doesn't typically affect vision but can help with diagnosis.

Diagnostic Approaches and Testing Options

Diagnosing Fabry disease can be challenging due to its rarity and the wide variety of symptoms that overlap with more common conditions. For males, the primary diagnostic test measures alpha-galactosidase A enzyme activity in blood samples. Low enzyme activity strongly suggests Fabry disease, though genetic testing is needed for confirmation.

For females, enzyme testing is less reliable as they can have normal or near-normal enzyme levels despite having the condition. Genetic testing for mutations in the GLA gene is the definitive diagnostic approach for both males and females. This testing is available through specialized laboratories such as Ambry Genetics, which offers comprehensive genetic analysis for lysosomal storage disorders including Fabry disease.

Additional diagnostic tools include kidney biopsies to assess Gb3 accumulation, echocardiograms to evaluate heart involvement, and ophthalmological exams to identify corneal whorling. Early diagnosis is crucial, as treatment is most effective when started before irreversible organ damage occurs.

Treatment Options and Management Strategies

The management of Fabry disease has evolved significantly with the introduction of enzyme replacement therapy (ERT). Two primary ERT options are available: agalsidase beta (Sanofi's Fabrazyme) and agalsidase alfa (Takeda's Replagal, not available in the US). These treatments involve regular intravenous infusions that replace the missing enzyme and help prevent further Gb3 accumulation.

Another treatment approach is oral chaperone therapy with migalastat (Amicus Therapeutics' Galafold), which works only for patients with specific amenable GLA mutations by helping the body's own defective enzyme fold correctly and function better.

Symptom management remains important alongside these specific therapies. Pain management may include anticonvulsants like carbamazepine or gabapentin. Kidney disease may require ACE inhibitors or angiotensin receptor blockers to reduce proteinuria, while advanced cases might need dialysis or transplantation. Cardiac symptoms often require standard heart medications, and stroke prevention measures are important for neurological protection.

Regular monitoring by a multidisciplinary team is essential, typically including nephrologists, cardiologists, neurologists, and genetic counselors. The Fabry Support & Information Group provides valuable resources and community support for patients navigating this complex condition.

Conclusion

Fabry disease presents with a complex constellation of symptoms that can significantly impact quality of life when left undiagnosed and untreated. From the characteristic burning pain in extremities to the potentially life-threatening cardiac and kidney complications, awareness of these symptoms is crucial for early intervention. If you or a family member experience multiple symptoms described in this article, especially with a family history of kidney disease, heart problems, or stroke at a young age, consider discussing Fabry disease testing with your healthcare provider. With advances in treatment options and increased diagnostic awareness, people with Fabry disease can now lead longer, healthier lives through proper management and care.

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This content was written by AI and reviewed by a human for quality and compliance.