About Fabry Disease

Fabry disease is a rare, inherited X-linked lysosomal storage disorder with multisystemic effects. The disease, also known as Anderson-Fabry disease, Morbus Fabry, and angiokeratoma corporis diffusum universale, was first described just over a century ago (Table 1).^[1,2]

Patients with Fabry disease have a defect in the gene for the lysosomal enzyme α-galactosidase A (α-GAL), also known as ceramide trihexosidase. This defect results in an inability or diminished ability to catabolize lipids with terminal α-galactosyl residues. In the absence of sufficient α-GAL, these lipids, particularly globotriaosylceramide (GL-3; also known as Gb3, ceramide trihexoside, and CTH), accumulate progressively in the lysosomes of many cell types throughout the body. ^[3,14] GL-3 accumulation in renal endothelial cells may play a role in renal failure. (Figure 1).

Progressive pathologic changes in the kidney result in renal failure by midlife in most classical Fabry cases. Before the availability of dialysis or transplantation, the average age of death for patients with classical Fabry disease was 41 years;^[16] today, average life expectancy is still only 50 years. ^[18]

Until the advent of enzyme replacement therapy, Fabry disease was managed by palliative and non-specific measures, such as analgesia, stroke prophylaxis, cardiac interventions, dialysis, and kidney transplantation. These measures still have a place in the management of Fabry disease; however, they do not address the lack of α-GAL and resultant intracellular GL-3 accumulation.

The availability of Fabrazyme^® (agalsidase beta) recombinant human α-GAL, provides an important, disease-specific treatment for patients with Fabry disease. Fabrazyme has been evaluated in several clinical trials. Studies completed to date demonstrate that Fabrazyme treatment results in significant GL-3 reduction from the vascular endothelium of the kidney, heart, and skin and from certain other cell types. GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels. Studies are ongoing to further evaluate the safety and efficacy of Fabrazyme.

For more comprehensive information about the clinical manifestations of this life-threatening disease, visit Signs and Symptoms.

For more comprehensive information about Fabry disease, please visit Genzyme’s Fabry Community website at www.fabrycommunity.com or use the Information Request feature to obtain medical literature.

^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. Fabry J. Ein Beitrag Zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa hemorrhagica Hebrae). Arch Dermatol Syphilis 1898;43:187-200.

2. Anderson W. A case of “Angeio-keratoma.” Brit J Dermatol 1898;10:113-7.

3. 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.

4. Pompen AWM, Ruiter M, Wyers HJG. Angiokeratoma corporis diffusum (universale) Fabry, as a sign of an unknown internal disease: two autopsy reports. Acta Med Scand 1947;128:234-55.

5. Sweeley CC, Klionsky B. Fabry’s disease: classification as sphingolipidosis and partial characterization of a novel glycolipid. J Biol Chem 1963;238:3148-50.

6. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;296:1163-7.

7. Kint JA. Fabry's disease: alpha-galactosidase deficiency. Science 1970;167:1268-9.

8. Desnick RJ, Dean KJ, Grabowski G, Bishop DF, Sweely CC. Enzyme therapy in Fabry disease: differential in vivo plasma clearance and metabolic effectiveness of plasma and splenic α-galactosidase A isozymes. Proc Natl Acad Sci U S A 1979;76:5326-30.

9. Bishop DF, Calhoun DH, Bernstein HS, Hanzopoulos P, Quinn M, Desnick RJ. Human α-galactosidase A: Nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci U S A 1986;83:4859-63.

10. Ohshima T, Murray GJ, Swaim WD, Longenecker G, Quirk JM, Cardarelli CO, Sugimoto Y, Pastan I, Gottesman MM, Brady RO, Kulkarni AB. α-Galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci U S A 1997;94:2540-4.

11. Ioannou YA, Zeidner KM, Gordon RE, Desnick RJ. Fabry disease: preclinical studies demonstrate the effectiveness of α-galactosidase A replacement in enzyme-deficient mice. Am J Hum Genet 2001;68:14-25.

12. Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, Gass A, Winston J, Dikman S, Fallon JF, Brodie S, Stacy CB, Mehta D, Parsons R, Norton K, O’Callaghan M, Desnick RJ. A Phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001;68:711-22.

13. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ. Safety and efficacy of recombinant human α-galactosidase A-replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9-16.56.

14. Peters FPJ, Vermeulen A, Kho TL. Anderson-Fabry’s disease: alpha galactosidase deficiency. Lancet 2001;357:138-40.

15. Colombi A, Kostyal A, Bracher R, Gloor F, Mazzi R, Tholen H. Angiokeratoma corporis diffusum – Fabry’s disease. Helv Med Acta 1967;34:67-83.

16. 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;38:750-60.