Fabry Disease

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). 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, angiokeratoma, 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, 3, 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, 6, 7]}

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.