Fabry disease has the potential to be fatal.

Overview

Fabry disease is inherited and caused by a fatty substance called globotriaosylceramide. Beginning in youth, this accumulation causes several physical ailments. Pain, particularly in the hands and feet (acroparesthesias); angiokeratomas, which are clusters of tiny, dark red spots on the skin; hypohidrosis; cloudiness or streaks in the front of the eye (corneal opacity or corneal verticillata); gastrointestinal problems; tinnitus, or ringing in the ears; and hearing loss are all symptoms of Fabry disease. Additional symptoms may vary by person.

Fabry disease can cause fatal renal, cardiac, and stroke problems. Some milder forms of the condition occur later in life and affect only the heart, kidneys, or brain blood vessels.

Facial dysmorphism in a Fabry disease patient

Disease frequency

Fabry disease is a rare genetic disorder, and its frequency varies depending on the population studied. People often cite the prevalence as 1 in 40,000–60,000 males. However, newborn screening studies suggest that the actual number of individuals with Fabry gene mutations may be higher than historical estimates. Fabry disease, being X-linked, can also affect females, albeit their symptoms and severity may differ.

How does Fabry disease affect daily life?

Fabry disease can significantly impact daily life, affecting physical, emotional, and social well-being. Here are some key ways it influences daily activities:

Chronic Pain & Fatigue: Many individuals experience burning pain in their hands and feet, making routine tasks difficult. Fatigue can also limit energy levels throughout the day.

Temperature Sensitivity: People with Fabry disease often struggle with heat and cold intolerance, making outdoor activities challenging.

Gastrointestinal Issues: Symptoms like nausea, diarrhea, and abdominal pain can interfere with meals and social interactions.

Skin & Appearance: The presence of angiokeratomas (red skin spots) may affect self-confidence.

Heart & Kidney Complications: Over time, Fabry disease can lead to heart problems and kidney dysfunction, requiring frequent medical checkups.

Mental Health Challenges: Coping with a chronic illness can lead to stress, anxiety, and depression.

Despite these challenges, treatment options and lifestyle adjustments can help improve quality of life. 

What is the inheritance of Fabry disease?

• Fabry disease is inherited in an X-linked manner, meaning the faulty gene is located on the X chromosome. 
• Since males (XY) have only one X chromosome, if they inherit the defective gene, they will develop Fabry disease. 
• Females (XX), on the other hand, have two X chromosomes, so if they inherit one faulty gene, their symptoms may range from mild to severe depending on how their normal X chromosome compensates.
• Affected fathers will always pass the mutated gene to their daughters but never to their sons.
• Mothers who are carriers or affected have a 50% chance of passing the gene to their sons and daughters.

These are common symptoms of Fabry disease.

Fabry disease can affect multiple organs and systems, leading to a wide range of symptoms. Some of the most common ones include

Neuropathic pain: Burning, tingling, or numbness in the hands and feet, often triggered by heat, stress, or exercise.

• Heat and cold intolerance: Difficulty regulating body temperature.
• Skin lesions (angiokeratomas): Small, dark red spots that typically appear on the lower trunk and thighs.
• Eye abnormalities: A whorled pattern in the cornea (cornea verticillata), which does not affect vision.
• Gastrointestinal issues: nausea, diarrhea, abdominal pain, and bloating.
• Kidney problems: Progressive kidney disease can potentially lead to kidney failure.
• Heart complications include an enlarged heart, an irregular heartbeat, and an increased risk of heart disease.
• Dizziness and fatigue: General weakness and flu-like symptoms.

Symptoms can vary widely between individuals, and females with Fabry disease may experience milder or more variable symptoms compared to males.

How is Fabry disease diagnosed?

Fabry disease is diagnosed through a combination of clinical evaluation, genetic testing, and enzyme activity measurement. Here’s how the process typically works:

*Enzyme Activity Test: In males, measuring the activity of alpha-galactosidase A in the blood can confirm the diagnosis. However, this test is less reliable for females, as they may have normal enzyme levels despite carrying the mutation.

*Genetic Testing: A DNA test can identify mutations in the GLA gene, which causes Fabry disease. The test is the most definitive way to diagnose both males and females.

*Biopsy and Imaging: In some cases, doctors may examine tissue samples or use imaging techniques to assess organ damage, particularly in the heart and kidneys.

*Newborn Screening: Some regions have started screening newborns for Fabry disease to enable early detection and treatment.

What specific tests are performed for Fabry disease?

Fabry disease is diagnosed using several specialized tests, including

• Lyso-Gb3 Analysis: A newer test that measures Lyso-Gb3 levels, which can help confirm the diagnosis and assess disease severity.
• Imaging Tests: MRI or echocardiography may be used to evaluate heart and kidney involvement.

What organ systems are most affected by Fabry disease?

Fabry disease affects multiple organ systems due to the accumulation of sphingolipids in cells. The most impacted systems include

• Cardiovascular system: Increased risk of arrhythmias, heart disease, and left ventricular hypertrophy.
• Nervous system: Neuropathic pain, stroke risk, and white matter lesions.
• Renal system: Progressive kidney dysfunction leading to potential failure.
• Gastrointestinal system: Abdominal pain, diarrhea, and difficulty digesting food.
• Dermatologic system: Presence of angiokeratomas (small dark red skin lesions).
• Ophthalmologic system: Cornea verticillata (whorled pattern in the cornea).
• Pulmonary system: Possible breathing difficulties.

What do positive test results imply for treatment options?

A positive test result for Fabry disease confirms the presence of a GLA gene mutation and guides treatment decisions. Here’s what it means for managing the condition:

Enzyme Replacement Therapy (ERT): This is the most common treatment, which gives patients the missing alpha-galactosidase, an enzyme that helps slow down the disease.

Chaperone Therapy (Migalastat): This oral medication helps stabilize the faulty enzyme, but it only works for certain genetic mutations.

Symptom Management: Medications for pain, gastrointestinal issues, heart complications, and kidney protection may be prescribed.

Lifestyle Adjustments: A low-sodium diet, hydration, and avoiding extreme temperatures can help manage symptoms.

Regular Monitoring: Patients need ongoing kidney, heart, and neurological assessments to track disease progression.

Early treatment can prevent organ damage and improve quality of life.

How does early diagnosis affect management?

Early diagnosis of Fabry disease is critical for effective management, as it allows for timely intervention to slow disease progression and prevent irreversible organ damage. Here’s how early detection impacts treatment:

• Initiation of Enzyme Replacement Therapy (ERT): Starting ERT early can help reduce the accumulation of harmful substances in cells, protecting the heart, kidneys, and nervous system.
• Better Symptom Control: Early intervention can reduce pain, gastrointestinal issues, and cardiovascular complications, improving quality of life.
• Preventing Severe Organ Damage: Delayed diagnosis often leads to irreversible kidney and heart disease, making early screening essential.
• Improved Prognosis: Patients diagnosed early tend to have better long-term outcomes, as treatment can be tailored before major complications arise.
• Family Screening: Because Fabry disease is genetic, early diagnosis enables the testing and, if necessary, treatment of family members.

Fabry disease treatment options are available.

Treatment for Fabry disease aims to control symptoms and slow the disease's progression. Here are the main options:

Enzyme Replacement Therapy (ERT): This replenishes the missing alpha-galactosidase A enzyme, helping to reduce the buildup of harmful substances in cells. The most common ERT is agalsidase beta (Fabrazyme), administered via infusion every two weeks.

Chaperone Therapy (Migalastat): An oral medication that helps stabilize the faulty enzyme, but it only works for specific genetic mutations.

Symptom Management: Medications for pain, gastrointestinal issues, heart complications, and kidney protection may be prescribed.

Lifestyle Adjustments: A low-sodium diet, hydration, and avoiding extreme temperatures can help manage symptoms.

Regular Monitoring: Patients need ongoing kidney, heart, and neurological assessments to track disease progression.

Conclusion

Fabry disease is a rare genetic condition that affects multiple organ systems due to the buildup of harmful substances in the body. Early diagnosis is crucial for effective management, as timely intervention can help slow disease progression and improve quality of life. Treatment options like enzyme replacement therapy (ERT) and chaperone therapy aim to address the underlying enzyme deficiency, while symptom management focuses on minimizing discomfort and complications.

Although Fabry disease can be difficult to live with, improvements in research and care give hope for a better future. Regular monitoring, lifestyle adjustments, and supportive care are essential for maintaining well-being. Raising awareness and promoting genetic testing can also help identify affected individuals and ensure timely intervention.