Overview

Fabry disease is a rare, inherited genetic disorder that affects the body's ability to break down a specific type of fat called globotriaosylceramide (GL-3 or Gb3). This buildup of fat occurs in the cells of blood vessels, skin, kidneys, heart, and nervous system, leading to a wide range of symptoms and complications. Fabry disease is classified as a lysosomal storage disorder and is caused by a deficiency or absence of the enzyme alpha-galactosidase A. The condition is progressive and can lead to serious organ damage over time if left untreated. It affects both males and females, though symptoms are often more severe in males.

Causes

Fabry disease is caused by mutations in the GLA gene located on the X chromosome. This gene provides instructions for producing the alpha-galactosidase A enzyme, which is responsible for breaking down GL-3. Without sufficient enzyme activity, GL-3 accumulates in cells, leading to widespread damage throughout the body.

• Inheritance Pattern: Fabry disease follows an X-linked inheritance pattern. Males with the defective gene typically show more severe symptoms because they have only one X chromosome. Females, having two X chromosomes, can be carriers and may experience mild to severe symptoms depending on X-inactivation patterns.
• Genetic Mutation: Over 900 different mutations in the GLA gene have been identified, leading to varying severity of the disease.

Symptoms

Symptoms of Fabry disease can vary widely in type and severity, and often appear in childhood or adolescence. Without treatment, symptoms generally worsen with age.

Common Symptoms Include:

• Pain (Acroparesthesias): Burning, tingling pain in hands and feet, often triggered by exercise, fever, or heat.
• Skin Lesions (Angiokeratomas): Clusters of small, dark red or purple spots, typically on the lower back, groin, or thighs.
• Decreased Sweating (Hypohidrosis): Reduced or absent ability to sweat, leading to heat intolerance.
• Eye Abnormalities: Cloudiness in the cornea (corneal verticillata), usually detected during an eye exam.
• Gastrointestinal Issues: Stomach pain, diarrhea, and bloating.
• Fatigue: Persistent tiredness due to chronic pain and organ involvement.

Advanced Symptoms and Complications:

• Kidney Disease: Progressive kidney damage can lead to renal failure.
• Heart Problems: Enlarged heart (cardiomyopathy), arrhythmias, and heart valve disease are common.
• Stroke: Increased risk of early stroke due to blood vessel involvement.
• Hearing Loss: Tinnitus and sensorineural hearing loss can develop.

Diagnosis

Early diagnosis of Fabry disease is crucial to prevent severe complications. Diagnosis involves clinical evaluation, laboratory tests, and genetic analysis.

• Enzyme Assay: Measures alpha-galactosidase A activity in blood. Males with Fabry disease usually have little to no enzyme activity.
• Genetic Testing: Confirms the diagnosis by identifying mutations in the GLA gene. Especially important in females, where enzyme levels may appear normal.
• Family History: Examination of family medical history helps identify affected relatives.
• Biopsy: Occasionally, tissue biopsy may show GL-3 accumulation in cells.
• Organ Function Tests: Kidney, heart, and brain assessments are often done to evaluate organ involvement.

Treatment

Although there is no cure for Fabry disease, several treatment options can effectively manage symptoms, slow progression, and improve quality of life.

• Enzyme Replacement Therapy (ERT): Regular infusions of synthetic alpha-galactosidase A (agalsidase beta or agalsidase alfa) help reduce GL-3 accumulation and alleviate symptoms.
• Chaperone Therapy: Migalastat is an oral medication used in specific mutations to stabilize the defective enzyme and improve function.
• Pain Management: Medications like anticonvulsants or antidepressants can help manage nerve pain.
• Kidney Support: ACE inhibitors or ARBs are used to protect kidney function and delay kidney failure.
• Cardiac Care: Treatment for arrhythmias, cardiomyopathy, and heart failure, including medications or devices like pacemakers.
• Stroke Prevention: Blood thinners or other therapies may be considered to reduce stroke risk.
• Supportive Care: Physical therapy, dietary adjustments, and counseling can aid in overall well-being.

Prognosis

The prognosis for Fabry disease varies depending on early diagnosis and treatment adherence.

• With Treatment: Early use of ERT or chaperone therapy can significantly slow disease progression, improve symptoms, and enhance quality of life.
• Without Treatment: The disease tends to progress over decades, leading to severe organ damage and reduced life expectancy, especially in males.
• Females: Prognosis in females is highly variable, ranging from mild to severe symptoms, but regular monitoring is essential.
• Ongoing Management: Lifelong follow-up with a multidisciplinary medical team is necessary to monitor organ function and adjust treatments as needed.

With advancements in treatment and supportive care, many individuals with Fabry disease can lead longer, more active lives than previously possible, particularly with early intervention.