About Fabry Disease

Introduction
Signs & Symptoms
Diagnosis
Treatment

Introduction
Fabry disease, also known as angiokeratoma corporis diffusum universale, Morbus Fabry, and Anderson-Fabry disease, was first described independently by Drs. William Anderson in England and Johann Fabry in Germany in 1898. Fabry disease is a rare, panethnic, X-linked recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-GAL). ^[1] Partial or complete deficiency of α-GAL leads to progressive accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in visceral tissues and the vascular endothelium throughout the body.^[1]

The inability to catabolize GL-3 leads to progressive multisystemic damage to the kidney, heart, and cerebrovascular system.^[1] The clinical course of Fabry disease is usually marked by chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke, and cardiac complications. As the disease progresses, complications may become life-threatening.

Since Fabry is X-linked, the disease predominantly affects males (hemizygotes), who have little if any endogenous α-GAL. Although X-linked recessive diseases generally do not affect females, there are female carriers (heterozygotes) who may experience varying degrees of disease manifestations. It is believed that X-chromosomal inactivation (lyonization), which can block expression of the functional α-GAL gene in all or some parts of the body, is responsible for disease onset in carriers.^[2-4] Although the prevalence of female carriers who develop overt clinical manifestations is unknown, recent studies indicate that manifestations in carrier females are more common than previously thought.^[5-7]

Signs & Symptoms
Signs and symptoms associated with Fabry disease are widely varied, making diagnosis challenging. Clinical onset usually occurs in childhood or adolescence, but symptoms are frequently misinterpreted or overlooked.^[8] Accurate diagnosis is frequently not established until adulthood, when the disease has progressed, and organ dysfunction or failure has occurred. ^[8]

The cardinal presenting features of Fabry disease are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas, hypohidrosis, heat and cold intolerance, and a characteristic "whorled" corneal opacity that does not affect vision. Progressive accumulation of GL-3 in the vascular endothelium and other tissues leads to life-threatening manifestations in adulthood involving the heart, kidneys, central and peripheral nervous system, and cerebrovascular system.^[9-11]

The list below provides an overview of the signs and symptoms of Fabry disease that may be seen at different stages of life. Both male and female patients may experience some or all of these manifestations to varying degrees, depending in part on the extent of alpha-GAL activity levels.^[8]

Childhood

• Episodic pain crises, acroparesthesia
• Hypohidrosis
• Corneal and lenticular opacities
• Recurrent fever
• Heat and cold intolerance

Adolescence

• Gastrointestinal manifestations
• Angiokeratomas
• Fatigue
• Episodic pain crises, acroparesthesia
• Hypohidrosis
• Corneal and lenticular opacities
• Recurrent fever
• Heat and cold intolerance

Adulthood

• Renal insufficiency/failure
• Neurological complications
• Cerebrovascular disease
• Cardiac dysfunction
• Hearing loss and tinnitus
• Gastrointestinal manifestations
• Angiokeratomas
• Fatigue
• Episodic pain crises, acroparesthesia
• Hypohidrosis
• Corneal and lenticular opacities
• Recurrent fever
• Heat and cold intolerance

Diagnosis

Presumptive Diagnosis
The following signs and symptoms are characteristic of Fabry disease and may lead to a presumptive clinical diagnosis:

• Distinctive dark red or purple spots (angiokeratomas), generally in the area between the abdomen and upper thighs
• Corneal opacities with a characteristic whorling pattern (observable through slit-lamp ophthalmoscopy)
• Symptoms of unexplained burning or tingling pain in the extremities (acroparesthesia); acute episodes of intense pain (Fabry crisis)
• Heat/cold intolerance; exercise intolerance
• Hypohidrosis/anhidrosis
• Premature renal insufficiency/failure with unknown etiology
• Cardiac abnormalities, especially left ventricular hypertrophy and mitral valve prolapse and/or regurgitation
• Premature stroke

Because Fabry disease is a multisystemic disorder, patients may present different symptoms to a wide range of specialists. The following table provides a list of specialists and the corresponding signs and symptoms that each physician may encounter.

Definitive Diagnosis
Once a presumptive diagnosis of Fabry disease has been made based on clinical signs and symptoms, definitive diagnosis can be made by testing for deficient α-GAL enzyme activity in plasma, leukocytes, tears, or biopsied tissue.^[1]

Treatment
Enzyme replacement therapy (ERT) is currently available in the United States and in over 27 additional countries for people with Fabry disease.

Disease management strategies may include medications and lifestyle approaches to symptom relief and interventions to delay serious sequelae due to organ damage (eg, kidney transplantation, cardiac pacemaker insertion).

References

1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001;3733-3774.

2. Bird TD, Lagunoff D. Neurological manifestations of Fabry disease in female carriers. Ann Neurol. 1978;4:537-540.

3. Grewal RP, McLatchey SK. Cerebrovascular manifestations in a female carrier of Fabry's disease. Acta Neurol Belg. 1992;92:36-40.

4. Van Loo A, Vanholder R, Madsen K, et al. Novel frameshift mutation in a heterozygous woman with Fabry disease and end-stage renal failure. Am J Nephrol. 1996;16:352-357.

5. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769-775.

6. Wendrich K, Whybra C, Ries M, Gal A, Beck M. Neurological manifestation of Fabry disease in females. Contrib Nephrol. 2001;136:241-244.

7. Whybra C, Wendrich K, Ries M, Gal A, Beck M. Clinical manifestation in female Fabry disease patients. Contrib Nephrol. 2001;136;245-250.

8. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol. 1995;12:215-219.

9. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001;3733-3774.

10. Okuda S. Renal involvement in Fabry's disease. Intern Med. 2000;39:601-602.

11. Grewal RP. Stroke in Fabry's disease. J Neurol 1994;241:153-156.

12. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol. 1995;12:215-219.