Diagnosis

Clinical heterogeneity and the rarity of Fabry disease make diagnosing Fabry disease a challenge. The age of presentation, presenting symptoms, and clinical course vary from individual to individual. Although symptoms generally appear in childhood, they may go unrecognized until adulthood when organ system damage has already occurred.^[1] Greater recognition of Fabry disease symptoms may lead to earlier suspicion and diagnosis, which in turn may result in more effective disease management.

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

Distinctive dark red or purple spots (angiokeratoma), 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.

One confounding factor in diagnosis is the fact that many common signs and symptoms of Fabry disease are misattributable to other conditions. The table below outlines some of the more common misdiagnoses of symptoms.

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. ^[2]

For more information about laboratories in Belgium where testing for deficient α-gal enzyme activity can be performed, see LSD specialized laboratories in Belgium

Although females carrying the Fabry gene may be asymptomatic or present with mild clinical manifestations, definitive identification of carriers is important. Diagnosis allows practitioners to monitor for new or worsening symptoms, and can help with identifying other family members with the disease.

Affected females can be diagnosed with Fabry disease by very low or absent α-GAL activity and by lipid deposition in biopsied tissues or urinary sediment. Many female carriers (with or without symptoms) have below-normal levels of α-GAL activity and/or the characteristic corneal opacities. However, this is not true for all carriers - some have α-GAL activity in the low to normal range. In families with an identified mutation, mutation analysis is the definitive way to identify carrier females. In families for whom a specific mutation is not documented, linkage analysis can be performed to establish carrier status. ^[3]

For more information about laboratories in Belgium where mutation analysis for Fabry can be performed, see LSD specialized laboratories in Belgium

Fabry disease can be diagnosed prenatally via cultured amniotic fluid cells and by chorionic villus sampling (at 9-10 weeks) and amniocentesis (at approximately 15 weeks).^[2]

References

1. 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.

2. 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.

3. Caggana M, Ashley GA, Desnick RJ, Eng CM. Fabry disease: molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at Xq22.1. Am J Med Genet. 1997;71:329-335.