Fabry Disease

Etiology

Researchers have identified hundreds of mutations in the gene encoding α-Gal A on the X chromosome that cause Fabry disease. Reduced or absent enzyme activity drives lysosomal accumulation of glycosphingolipids, primarily cerebroside trihexosides, within multiple tissues.

Progressive glycolipid deposition promotes endothelial cell swelling and proliferation, ultimately resulting in renal failure during the third to fourth decade of life, along with cardiac disease, cerebrovascular events, and premature death. Mutations producing the classic Fabry phenotype lead to widespread multisystem involvement. In contrast, milder variants associated with missense mutations demonstrate a more limited presentation, with disease manifestations largely confined to cardiac abnormalities.[2]

Epidemiology

Prevalence in white male populations has been reported to range from approximately 1:17,000 to 1:117,000 for Fabry disease. Classic Fabry disease mutations are seen in approximately 1:22,000 to 1:40,000 males, and atypical presentations are associated with about 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females.

According to targeted screening programs, evaluating patients on dialysis and newborn screening for enzyme activity suggests that atypical later-onset Fabry disease predominantly affects the cardiovascular, cerebrovascular, or renal systems. Newborn screening in northern Italy had an incidence of 1:7,879 newborns; all individuals had the later-onset or an unclassified variant of Fabry disease. The incidence in Washington State and Illinois was similar at 1:6,000 to 1:9,000 individuals, whereas the incidence in Missouri was 1:2,913 to 1:3,277 individuals. The incidence in Hungary, Austria, and Spain was 1:3,000 to 1:4,000 individuals

Pathophysiology

The precise mechanisms underlying the pathogenesis of Fabry disease remain incompletely defined. Fabry disease belongs to the group of X-linked inherited lysosomal storage disorders characterized by α-Gal A deficiency, which leads to lysosomal accumulation of globotriaosylceramide (Gb3). Fibrosis, inflammation, and oxidative stress contribute significantly to the disease process. Accumulation of lysosomal Gb3 promotes nitric oxide release, a factor implicated in the development of vasculopathy.

Glycosphingolipid deposition within other tissues, including macrophages and lymphocytes, contributes to inflammatory responses, oxidative injury, and progressive tissue damage. Organs most frequently affected include the skin, heart, kidneys, and brain. In the kidneys, Gb3 accumulates predominantly in the glomeruli, followed by deposits in the distal tubules. This distribution correlates with the early development of proteinuria and polyuria. The mechanisms underlying renal sinus cyst formation in Fabry disease remain poorly understood.[3]

Histopathology

Various biopsies may be performed to evaluate patients for Fabry disease histologically. Skin biopsy typically demonstrates increased lipid content within affected tissues. Lipid deposits may also appear within muscle fibers, endothelial cells, and ganglion cells.[4] Histologic examination commonly reveals small-vessel angiomas resulting from cumulative vascular cell injury within the dermis, accompanied by vessel dilation.

Renal biopsy demonstrates globotriaosylceramide accumulation within podocytes, highlighted by special staining techniques and most clearly visualized on electron microscopy, where characteristic intracellular inclusions become apparent.[5] Endomyocardial biopsy allows identification of characteristic globotriaosylceramide inclusions within cardiac tissue. Detection of these inclusions can establish the diagnosis in patients presenting with left ventricular hypertrophy or heart failure.

History and Physical

Clinical assessment is an essential component of the evaluation of Fabry's disease. A thorough medical history can reveal clinical features associated with this condition, including high blood pressure with renal dysfunction. Clinical history should be taken with specific attention to heat intolerance, abnormal decreases in sweat and tear production, and cerebrovascular accident. Clinicians should consider genetic counseling in particular, given the X-linked pattern of inheritance. 

Affected males often develop Fabry disease during childhood or early adolescence, with potential involvement of any organ system. Clinical presentation commonly includes painful acroparesthesias, hypohidrosis, and gastrointestinal symptoms, eg, abdominal cramping and diarrhea. Cutaneous manifestations consist of microvascular lesions that may appear as small petechiae around the umbilicus. Ocular involvement includes lenticular opacities and corneal dystrophy.

Disease progression varies among individuals but frequently includes polyuria, polydipsia, and proteinuria, advancing to end-stage renal disease, cardiac conduction abnormalities, valvular defects, cerebrovascular accidents, and other neurological manifestations during the third to fourth decade of life. Additional complaints may include lymphadenopathy and difficulty tolerating heat or cold exposure, as well as reduced tolerance for strenuous exercise.

Evaluation

Clinicians should maintain a high index of suspicion for Fabry disease in individuals presenting with the previously described signs and symptoms, supported by findings from a comprehensive personal and family history and detailed physical examination. Initial evaluation benefits from a basic metabolic panel assessing electrolyte balance and renal function, urine sediment analysis for oval fat bodies, electrocardiography, and echocardiography to identify conduction or structural abnormalities.

Radiologic studies, including chest x-ray, computed tomography (CT), CT angiography, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and MR spectroscopy, may support evaluation of neurological involvement. Definitive diagnosis requires demonstration of reduced α-Gal A activity in leukocytes or plasma. When enzyme assays or genetic testing are unavailable, a skin or kidney biopsy may establish the diagnosis by identifying characteristic glycolipid deposits. Electron microscopy of renal biopsy specimens reveals concentric lamellar inclusions, commonly referred to as myeloid or zebra bodies.[6]

Treatment / Management

Fabry disease is completely incurable. The patient needs supportive treatment by replacing the deficient enzyme α-Gal A (alpha or beta) as soon as the diagnosis is made, regardless of the presence or absence of clinical manifestations in affected males and patients on renal replacement therapy. Female carriers and affected males with decreased α-Gal A levels should receive enzyme replacement only in the presence of kidney, heart, or neurological features. Patients on long-term dialysis should also receive enzyme replacement therapy. Hypertension in these patients should be managed with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.[7](B3)

Either enzyme alpha or enzyme beta replacement infusions should be given every 2 weeks, based on body weight calculations. Precautions should be taken considering infusion-related reactions. Slow infusion over 1 to 2 hours, along with prior administration of antipyretics, should be considered.[7] Additionally, patients with Fabry disease and end-stage renal disease can be safely considered for renal transplantation with the continued enzyme replacement posttransplant.(B3)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating patients for Fabry disease include:

• Stroke
• Cavernous sinus syndromes
• Lacunar syndromes
• Multiple sclerosis

Prognosis

Following the occurrence of a first stroke, affected individuals face a heightened risk of recurrent cerebrovascular events. Heterozygous females typically have a milder clinical course than males, with fewer and less severe manifestations of the disease.

Complications

Complications of Fabry disease include:

• Angiokeratomas
• Cardiomegaly
• Arrhythmias
• Acroparesthesia
• Hearing loss
• Vertigo
• Altered sweating
• Corneal verticillata