What is Fabry disease?

What is Fabry Disease?

Fabry disease is an X-linked recessive lysosomal storage disorder caused by deficient α-galactosidase A enzyme activity, resulting in progressive accumulation of globotriaosylceramide (Gb3) in tissues throughout the body, particularly in vascular endothelium, leading to life-threatening renal, cardiac, and cerebrovascular complications. 1

Genetic and Biochemical Basis

• The disease results from mutations in the GLA gene, which encodes the lysosomal enzyme α-galactosidase A (α-Gal A), impairing the degradation of glycosphingolipids 2, 3
• Males with classic phenotype have very low or undetectable α-Gal A activity, while patients with detectable enzyme activity present with a milder, variant phenotype 1
• The accumulation of Gb3 and its deacylated form (lyso-Gb3) begins prenatally and progressively deposits in various cell types, creating electron-dense vesicles visible on electron microscopy 2, 4

Inheritance Pattern and Epidemiology

• The disease is X-linked recessive and predominantly affects males, though heterozygous females can be affected from mildly to severely due to random X-chromosomal inactivation 1
• The estimated incidence ranges from 1 in 40,000 to 60,000 males across all ethnic groups 1
• Female carriers may develop symptoms as severe as males, though typically about a decade later 5

Clinical Manifestations by Organ System

Early Childhood Symptoms (6-8 years)

• Neuropathic pain is typically the first manifestation, with episodes of acute pain (Fabry crises) and chronic acroparesthesias affecting hands and feet 2, 1
• Hypohidrosis (reduced sweating) is frequent, leading to heat and exercise intolerance related to autonomic dysfunction 2, 1
• Gastrointestinal symptoms include abdominal pain and diarrhea 2, 1

Dermatologic Findings

• Angiokeratomas (small, dark red skin lesions) appear, particularly in the "bathing trunk" distribution 5

Progressive Multi-Organ Involvement

Renal manifestations:

• Early and substantial Gb3 deposition occurs in podocytes, leading to proteinuria beginning in childhood or adolescence 4, 1
• Progressive accumulation in glomerular endothelium, mesangium, and tubular epithelium leads to end-stage renal disease 1, 4

Cardiac manifestations:

• Glycosphingolipid deposits in cardiomyocytes cause concentric left ventricular hypertrophy without dilation 1, 5
• Conduction system involvement leads to arrhythmias, with characteristic ECG findings including short PR interval and QRS widening 1, 5
• Valvular involvement affects mitral and aortic valves 5

Cerebrovascular manifestations:

• Vascular endothelial accumulation leads to ischemia and infarction of small vessels, resulting in strokes and transient ischemic attacks 1
• White matter lesions and cerebrovascular events occur with increasing frequency 3, 6

Ophthalmologic findings:

• Corneal verticillata (whorl-like opacities) and lens opacities develop from deposits in epithelial cells 1

Pathophysiology of Vascular Complications

• The primary mechanism of organ damage is progressive lysosomal accumulation in vascular endothelium, leading to vessel occlusion, ischemia, and infarction 1
• Endothelial dysfunction and a prothrombotic state contribute to the vasculopathy 1, 5

Diagnostic Approach

For males:

• Diagnosis is confirmed by demonstrating deficient α-Gal A activity in leukocytes or plasma 2, 3
• Elevated Gb3 levels in plasma and urine sediment serve as biomarkers 2

For females:

• Molecular genetic analysis identifying pathogenic GLA mutations is the diagnostic gold standard, as enzymatic activity may be normal due to X-inactivation patterns 2, 3

Natural History Without Treatment

• Progressive Gb3 accumulation leads to irreversible organ damage in the kidneys, heart, and brain 2, 1
• Death typically occurs in the fifth to sixth decade of life from renal failure, cardiac events, or cerebrovascular complications 2

Common Diagnostic Pitfalls

• The disease is frequently misdiagnosed in childhood, with symptoms attributed to rheumatic fever, erythromelalgia, neurosis, Raynaud syndrome, multiple sclerosis, lupus, or growing pains 1
• Diagnosis is often delayed until adulthood (average age 29 years), when irreversible organ damage has already occurred 1
• Female carriers are commonly overlooked despite potentially severe manifestations 5

Treatment Implications

• Enzyme replacement therapy (ERT) with recombinant human α-Gal A is the disease-specific treatment that can reverse substrate storage in lysosomes 1
• ERT should be initiated as early as possible in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial manifestations, ideally before irreversible organ damage occurs 1, 2
• For children, treatment should begin at the onset of clinically significant symptoms 2
• Oral chaperone therapy with migalastat is available for patients with amenable GLA mutations, offering an alternative to intravenous ERT 3, 6, 7