Genetics and Inheritance

Estimates of the incidence of Fabry disease range from 1 in 40,000 males^[8], to 1 in 117,000 in the general population,^[1] and the disease is panethnic. Since Fabry disease is X-linked, it predominantly affects males, although females may have disease manifestations to a greater extent than previously thought.^[2,3] Males with Fabry disease (hemizygotes) pass the defective gene on to all of their daughters and none of their sons. (Figure 1) Females (heterozygotes) have a 50% chance of passing on the defective gene to both their sons and their daughters (Figure 2).

Virtually all males with the defective gene develop the disease.^[4] Some females will develop signs and symptoms of Fabry disease due to variability of the X-chromosomal inactivation within cells. The rates of progression of organ impairment may be slower than in males with Fabry disease, and severity of signs and symptoms is variable.

The defects in the α-GAL gene are heterogeneous, and most families have private mutations.^[5,6] About 300 mutations of the α-GAL gene (locus Xq22.1) have been recorded in the Human Mutation Database.^[7] The wide range of mutations may explain variations in clinical presentation; therefore, efforts to establish phenotype/genotype correlations have been limited.^[6,8,9]

^{Figure 1}

^{Figure 2}

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

2. 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;38:769-807.

3. Wendrich K, Whybra C, Ries M, Gal A, Beck M. Neurological manifestation of Fabry disease in females. Contrib Nephrol 2001;136:241-4.

4. Van Loo A, Vanholder R, Madsen K, Praet M, Kint J, De Paepe A, Messiaen L, Lameire N, Hasholt L, Sorensen SA, Ringoir S. Novel frameshift mutation in a heterozygous woman with Fabry disease and end-stage renal failure. Am J Nephrol 1996;16:352-7.

5. 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.

6. Brown LK, Miller A, Bhuptani A, Sloane MF, Zimmerman MI, Schilero G, Eng CM, Desnick RJ. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med 1997;155:1004-10.

7. The Human Gene Mutation Database. www.hgmd.org.

8. 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.

9. Knol IE, Ausems MG, Lindhout D, van Diggelen OP, Verwey H, Davies J, Ploos van Amstel JK, Poll-The BT. Different phenotypic expression in relatives with Fabry disease caused by a W226X mutation. Am J Med Genet 1999;82:436-9.