About Fabry Disease

^Description

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 alpha-galactosidase A (alpha-GAL).^[1] Partial or complete deficiency of alpha-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 alpha-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 alpha-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]

Although classical Fabry disease usually presents in childhood (with pain, fever, hypohidrosis, fatigue, and exercise intolerance) diagnosis may not be confirmed until there has been considerable accumulation of GL-3. The average age of diagnosis is approximately 30 years.^[8] Delayed diagnosis may be due in part to under-recognition of the disease and/or misattribution of Fabry disease symptoms to other disorders.

Progressive organ and tissue damage associated with Fabry disease may result in substantially decreased life expectancy. Before the availability of renal dialysis or transplantation, the average age of death among patients with classical Fabry disease was 41 years;^[9] today, average life expectancy is still only 50 years.^[10]

Growing evidence indicates there may be a significant number of “atypical variants” — hemizygotes who have few or none of the hallmark symptoms of classical Fabry disease.^[11-15] Atypical variants have residual plasma alpha-GAL levels (1% to 30% of normal)^[12-15] and present much later in life than patients with classical Fabry disease. They are often identified serendipitously, and usually have manifestations predominately in one organ system. More information about the cardiac variant, the most recognized atypical variant of Fabry disease, is presented in the Cardiac Dysfunction section.

The Signs and Symptoms section of this site presents the common manifestations of Fabry disease.

^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. Morgan SH, Crawfurd MA. Anderson-Fabry disease. BMJ. 1988;297:872-873.

9. Colombi A, Kostyal A, Bracher R, Gloor F, Mazzi R, Tholen H. Angiokeratoma corpus diffusum - Fabry's disease. Helv Med Acta. 1967;34:67-83.

10. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750-760.

11. Chimineti C, Ricci R, Pieroni M, Natale L, Russo MA, Frustaci A. Cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy. Cardiologia. 1999;44:469-473.

12. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, Olsen EG, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-9.

13. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288-293.

14. Yoshitama T, Nakao S, Takenaka T, et al. Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease. Am J Cardiol. 201;87:71-75.

15. Nagao Y, Nakashima H, Fukuhara Y, et al. Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase A. Clin Genet. 1991;39:233-237.