Fabry Disease

Overview

Plain-Language Overview

Fabry Disease is a rare inherited disorder that affects how the body breaks down certain fats. It happens because of a problem with an enzyme called alpha-galactosidase A, which leads to a buildup of a fatty substance in the body's cells. This buildup can cause pain, especially in the hands and feet, and can affect the skin, kidneys, heart, and nervous system. People with Fabry Disease may notice small, dark red spots on their skin and experience episodes of burning pain. The condition can vary widely in how it affects individuals, with some experiencing severe symptoms and others having milder issues.

Clinical Definition

Fabry Disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, resulting in deficient activity of the enzyme alpha-galactosidase A. This enzymatic deficiency leads to systemic accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids within lysosomes of vascular endothelial cells, smooth muscle cells, renal epithelial cells, cardiomyocytes, and neurons. Clinically, Fabry Disease manifests with neuropathic pain, angiokeratomas, hypohidrosis, corneal verticillata, and progressive renal impairment. Cardiac involvement includes left ventricular hypertrophy and arrhythmias, while cerebrovascular complications such as transient ischemic attacks and strokes are common. Diagnosis is confirmed by measuring alpha-galactosidase A activity in males or genetic testing in females. The disease exhibits variable expressivity and incomplete penetrance, particularly in heterozygous females. Early diagnosis is critical to prevent irreversible organ damage. Enzyme replacement therapy and chaperone therapy are current treatment modalities aimed at reducing substrate accumulation and improving clinical outcomes.

Inciting Event

Fabry disease is a genetic disorder; no external inciting event is required.

Latency Period

none

Diagnostic Delay

Variable and nonspecific early symptoms such as neuropathic pain and gastrointestinal complaints lead to misdiagnosis.
Lack of awareness and rarity of the disease contribute to delayed enzyme testing and diagnosis.
Symptoms may be attributed to more common conditions like fibromyalgia or chronic kidney disease of other causes.

Clinical Presentation

Signs & Symptoms

Neuropathic pain crises and burning sensations in the hands and feet (acroparesthesias).
Angiokeratomas appearing as clusters of small, dark red skin lesions.
Hypohidrosis or anhidrosis leading to heat intolerance.
Gastrointestinal symptoms including diarrhea and abdominal pain.
Progressive renal impairment with proteinuria.
Cardiac symptoms such as arrhythmias and heart failure.
Hearing loss and tinnitus.
Corneal verticillata causing no visual impairment but detectable on exam.

History of Present Illness

Chronic, burning neuropathic pain in the hands and feet (acroparesthesias).
Episodes of pain crises triggered by fever, exercise, or stress.
Progressive proteinuria and renal impairment.
Gastrointestinal symptoms including abdominal pain and diarrhea.
Hypohidrosis or anhidrosis leading to heat intolerance.
Cardiac symptoms such as palpitations, chest pain, or exertional dyspnea.

Past Medical History

History of angiokeratomas, small dark red skin lesions typically in the groin or lower trunk.
Previous episodes of corneal verticillata (whorled corneal opacities) detected on eye exam.
Chronic kidney disease or unexplained proteinuria.
History of stroke or transient ischemic attacks at a young age.

Family History

X-linked inheritance pattern with affected male relatives on the maternal side.
Female relatives may have milder or variable symptoms due to lyonization.
Family history of unexplained renal failure, early stroke, or hypertrophic cardiomyopathy.

Physical Exam Findings

Presence of characteristic angiokeratomas, small dark red to black papules typically found in the bathing trunk area.
Corneal verticillata (whorled corneal opacities) visible on slit-lamp eye examination.
Mild hypohidrosis or anhidrosis noted on skin examination.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Fabry Disease requires demonstration of deficient alpha-galactosidase A enzyme activity in males or identification of a pathogenic GLA gene mutation in females, supported by clinical features such as neuropathic pain, angiokeratomas, corneal verticillata, and evidence of organ involvement including renal dysfunction, cardiac hypertrophy, or cerebrovascular disease.

Pathophysiology

Key Mechanisms

Fabry disease is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, leading to accumulation of globotriaosylceramide (Gb3) in various tissues.
The buildup of glycosphingolipids in vascular endothelial cells causes progressive vascular dysfunction and organ damage.
Accumulation in the renal glomeruli and tubules leads to progressive kidney failure.
Deposition in the cardiac myocytes results in hypertrophic cardiomyopathy and conduction abnormalities.
Involvement of peripheral nerves causes neuropathic pain and autonomic dysfunction.

Involvement	Details
Organs	Kidneys are commonly affected, leading to proteinuria and eventual renal failure.
	Heart involvement includes hypertrophic cardiomyopathy and arrhythmias.
	Skin shows angiokeratomas due to vascular endothelial lipid deposits.
	Nervous system involvement causes neuropathic pain and autonomic dysfunction.
Tissues	Vascular tissue is affected by lipid accumulation causing ischemia and pain.
	Renal tissue undergoes progressive damage leading to chronic kidney disease.
	Cardiac tissue develops hypertrophy and fibrosis resulting in heart failure.
Cells	Endothelial cells accumulate globotriaosylceramide leading to vascular dysfunction.
	Podocytes in the kidney are damaged by lipid accumulation causing proteinuria and renal failure.
	Cardiomyocytes accumulate lipid deposits contributing to hypertrophic cardiomyopathy.
Chemical Mediators	Globotriaosylceramide (Gb3) is the primary lipid that accumulates due to alpha-galactosidase A deficiency.
Chemical Mediators	Lyso-Gb3 is a deacylated form of Gb3 that contributes to cellular toxicity and inflammation.

Treatment

Pharmacological Treatments

Enzyme replacement therapy (agalsidase beta or agalsidase alfa)
- Mechanism: Replaces deficient alpha-galactosidase A enzyme to reduce globotriaosylceramide accumulation
- Side effects: infusion reactions, hypersensitivity, headache, fever
Chaperone therapy (migalastat)
- Mechanism: Stabilizes certain mutant forms of alpha-galactosidase A to enhance its activity
- Side effects: headache, nausea, urinary tract infection

Non-pharmacological Treatments

Regular monitoring of renal function and cardiac status to manage disease progression.
Pain management through physical therapy and lifestyle modifications to reduce neuropathic pain triggers.
Genetic counseling for affected families to understand inheritance patterns and reproductive options.

Prevention

Pharmacological Prevention

Enzyme replacement therapy with recombinant alpha-galactosidase A to reduce substrate accumulation.
Chaperone therapy (e.g., migalastat) for amenable GLA mutations to stabilize enzyme function.
Use of ACE inhibitors or ARBs to slow progression of renal disease.
Antiarrhythmic drugs and beta-blockers to manage cardiac complications.

Non-pharmacological Prevention

Regular monitoring of renal, cardiac, and neurological function to detect early complications.
Avoidance of heat exposure and strenuous exercise to reduce pain crises.
Genetic counseling for affected families to inform reproductive decisions.
Lifestyle modifications including blood pressure control and smoking cessation.

Outcome & Complications

Complications

End-stage renal disease requiring dialysis or transplantation.
Progressive cardiomyopathy leading to heart failure.
Life-threatening arrhythmias and sudden cardiac death.
Ischemic stroke from small vessel disease.
Chronic pain and disability from neuropathy.

Short-term Sequelae	Long-term Sequelae
Acute pain crises causing severe neuropathic pain episodes. Transient gastrointestinal symptoms such as diarrhea and cramping. Episodes of hypohidrosis leading to heat intolerance.	Chronic renal failure progressing to end-stage kidney disease. Irreversible cardiac fibrosis and heart failure. Permanent neuropathy with sensory loss and pain. Cerebrovascular disease causing stroke and cognitive decline.

Differential Diagnoses

Fabry Disease versus Gaucher Disease

Fabry Disease	Gaucher Disease
Fabry disease presents with angiokeratomas and acroparesthesias rather than bone crises.	Presence of hepatosplenomegaly and bone crises in a patient with Gaucher disease.
Deficiency of alpha-galactosidase A causing accumulation of globotriaosylceramide.	Deficiency of the enzyme glucocerebrosidase leading to accumulation of glucocerebroside.
Presence of corneal verticillata (whorled corneal opacities) is typical in Fabry disease.	Characteristic Gaucher cells with crumpled tissue paper cytoplasm seen on bone marrow biopsy.

Fabry Disease versus Metachromatic Leukodystrophy

Fabry Disease	Metachromatic Leukodystrophy
Fabry disease primarily affects small vessels causing pain and skin lesions rather than CNS demyelination.	Deficiency of arylsulfatase A leading to accumulation of sulfatides causing demyelination.
Fabry disease presents with angiokeratomas and renal involvement rather than progressive cognitive decline.	Progressive neurologic decline with motor and cognitive impairment.
MRI in Fabry disease may show vascular changes but not diffuse white matter demyelination.	MRI shows white matter demyelination predominantly in the central nervous system.

Fabry Disease versus Pompe Disease

Fabry Disease	Pompe Disease
Fabry disease involves vascular endothelial cells and presents with neuropathic pain and skin lesions.	Deficiency of acid alpha-glucosidase causing glycogen accumulation in lysosomes.
Fabry disease shows alpha-galactosidase A deficiency rather than glycogen storage.	Presentation includes cardiomegaly, hypotonia, and muscle weakness in infants.
Cardiac involvement in Fabry disease is due to glycosphingolipid deposition, not glycogen accumulation.	Elevated creatine kinase (CK) and evidence of glycogen storage in muscle biopsy.