Diagnosis

^{Classical Fabry Disease}

Although classical Fabry disease usually presents in childhood, with pain, fever, hypohidrosis, fatigue, and/or exercise intolerance, the disease often goes unrecognized by physicians until adulthood, when the underlying pathology is advanced. ^[1,2]In a study of 30 large pedigrees, the mean age of diagnosis of index cases was 29 years. ^[3] A second, more recent study of prevalence of lysosomal storage disorders in Australia from 1980 through 1996 found the median age of diagnosis of Fabry disease to be 28.6 years. ^[4] Delayed diagnosis may be due to under-recognition of the disease.

In addition, Fabry disease symptoms are often mistaken for those of other disorders, such as rheumatoid or juvenile arthritis, rheumatic fever, erythromelalgia, neurosis, Raynaud’s syndrome, multiple sclerosis, lupus, acute appendicitis, “growing pains” or malingering, petechiae, or collagen vascular disease. The table below shows lists of symptoms of Fabry disease that are commonly associated with other disorders. In patients with these symptoms, a differential diagnosis of Fabry disease should be considered. ^[3,5,6,7-9]

Clinical diagnosis of classical Fabry disease is based upon some (or all) of the following: family history, history of childhood fevers in association with pain in the extremities, the characteristic skin lesions (angiokeratomas), the characteristic “whorled” corneal opacity, and the presence of lipid-laden cells in urinary sediment or biopsied tissues. In males, diagnosis is confirmed biochemically by demonstration of very low or undetectable α-GAL activities in plasma, serum, leukocytes, tears, or biopsied tissue, using an assay with a synthetic substrate of α-GAL and with N-acetylgalactosamine in the reaction mixture to inhibit α-N-acetylgalactosaminidase (alpha-galactosidase B) activity. ^[11] See below for information on diagnosis for females.

Given the progressive nature of Fabry disease, early diagnosis is important. Once a diagnosis is made, a medical family pedigree can be developed and families can be directed to diagnostic, therapeutic, and support services, including genetic counseling.

^{Female Heterozygotes With and Without Clinical Manifestations}

It is important to recognize that although most patients with classical Fabry disease are male, females can also have classical Fabry disease.

The majority of female heterozygotes (with or without manifestations) have below normal levels of α-GAL activity and the characteristic “whorled” corneal opacity.^[5]

However, absence of these clinical indicators does not preclude Fabry carrier status, since some female heterozygotes have tissue-specific normal α-GAL activity. ^[12] In Fabry kindreds with a known mutation, mutation analysis can identify female heterozygotes . In families for whom a specific mutation is not documented, linkage analysis can be performed to establish carrier status. ^[13]

^{Atypical Variants}

Atypical variants can be identified by low α-GAL activity.^[5,14] These patients may be diagnosed after the onset of cardiac or renal manifestations.

^{Prenatal Diagnosis}

Hemizygotes can be identified parentally by assaying for an XY karyotype and deficient α-GAL activity in chorionic villi (obtained in the ninth to tenth week of pregnancy) or in cultured amniotic cells obtained through amniocentesis (at 15 weeks of pregnancy).^[15] Heterozygotes can be identified parentally if the family mutation is known.

^Indication

Fabrazyme^® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

Important Safety Information Fabrazyme (agalsidase beta) is indicated for use in patients with Fabry disease.  Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established. The most serious and most common adverse reactions reported with Fabrazyme are infusion reactions.  Serious and/or frequently occurring related adverse reactions consisted of one or more of the following events: chills, pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence. The occurrence of somnolence can be attributed to clinical trial specified pre-treatment with antihistamines.  Other reported serious adverse events included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome.  These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied. Infusion reactions occurred in many patients treated with Fabrazyme and some of the reactions were severe.  Patients should be given antipyretics prior to infusion.  Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.  Infusion reactions declined in frequency with continued use of Fabrazyme.  However, infusion reactions may still occur despite extended duration of Fabrazyme treatment.  Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.  Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme. Most patients develop IgG antibodies to Fabrazyme.  A few patients developed IgE or skin test reactivity specific to Fabrazyme.  Physicians should consider testing for IgE in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti- Fabrazyme IgE.   Patients with Fabrazyme- specific IgE antibody have been treated using a rechallenge protocol.  Rechallenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available. The safety and efficacy in patients younger than 8 years of age have not been evaluated.  IgE immunologic responses in pediatric patients may differ from those in adults, as IgG seroconversion was associated with prolonged half-life concentrations of Fabrazyme, which is rarely observed in adult patients. Fabrazyme is available by prescription only. Side effects should be reported promptly to Genzyme Medical Information at 800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Genzyme at 1-800-745-4447.

^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;12:215-9.

2. Menkes DL, O'Neil TJ, Saenz KK. Fabry's disease presentingas syncope, angiokeratomas, and spoke-like cataracts ina young man: discussion of the differential diagnosis. Mil Med 1997;162:773-6.

3. Morgan SH, Crawfurd MA. Anderson-Fabry disease. BMJ 1988;297:872-3.

4. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249-54.

5. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 2001;3733-74.

6. Whybra C, Wendrich K, Ries M, Gal A, Beck M. Clinical manifestation in female Fabry disease patients. Contrib Nephrol 2001;136:245-50.

7. Morgan SH, Crawfurd MA. Anderson-Fabry disease. BMJ 1988;297:872-3.

8. Peters FPJ, Sommer A, Vermeulen A, Cheriex EC, Kho TL. Fabry’s disease: a multidisciplinary disorder. Postgrad Med J 1997;73:710-2.

9. Kolodny EH. Fabry diseas. In: Bogousslavsky J, Caplan L, eds. Stroke Syndromes. New York: Cambridge University Press 1995; 453-9.

10. Stryker VL, Kreps C. Fabry disease. Am J Nurs 2001;101:39-44.

11. Mayes JS, Scheerer JB, Sifers RN, Donaldson ML. Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry’s disease. Clin Chim Acta 1981;112:247-51.

12. Ashton-Prolla P, Ashley GA, Giugliani R, Pires RF, Desnick RJ, Eng CM. Fabry disease: comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG). Am J Med Genet 1999;84:420-4.

13. 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.

14. Walters BAJ, Prichard M, McCardle H, Richards SM, Bosch JP. Prevalence of reduced plasma α-galactosidase activity in a cohort of male patients on hemodialysis (HD) in the United States. Abstract presented at Annual Clinical Genetics Meeting, 2002.

15. Brady RO, Uhlendorf BW, Jacobson CB. Fabry’s disease: antenatal detection. Science 1971; 172:174-5.