Fabry Disease

Fabry disease is an X-linked genetic disorder with multisystemic effects. Patients with Fabry disease have a defect in the gene for the lysosomal enzyme α-galactosidase A (α-GAL). This defect causes an inability or diminished ability to catabolize globotriaosylceramide (GL-3). As a result, GL-3 accumulates progressively in the lysosomes of many cell types throughout the body.1,2 Fabry disease is one of about 40 diseases classified as lysosomal storage disorders.3

GL-3 accumulation starts early in life and continues over decades, causing heterogenous symptoms that often go unrecognized until adulthood, when organ system damage may have occurred.1 Early symptoms may include episodic crises of pain, acroparesthesia, angiokeratomas, corneal and lenticular opacities, gastrointestinal problems, and tinnitus or hearing loss. By the fourth to fifth decade, life-threatening renal, cardiac, and cerebrovascular complications typically occur. For more information on specific signs and symptoms, please see Information for Specialists.

Until the advent of enzyme replacement therapy, Fabry disease was managed only by palliative and non-specific measures, such as analgesia, stroke prophylaxis, cardiac interventions, dialysis, and kidney transplantation. These measures are still important 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 that lowers GL-3 in patients with Fabry disease. Fabrazyme has been evaluated in several clinical trials. Studies completed to date demonstrate that Fabrazyme treatment results in GL-3 reduction from the vascular endothelium of the kidney, heart, and skin and from certain other cell types. Sanofi Genzyme continues to collect safety and efficacy data on Fabrazyme.

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.

Inheritance

Estimates of the incidence of Fabry disease range from 1 in 40,000 males1 to 1 in 117,000 in the general population.3 The disease is panethnic. Since Fabry disease is X-linked, it was previously thought to affect only males, with females generally considered to be asymptomatic carriers. Research shows that most females who carry the defective gene are clinically affected.4-11

Males with Fabry disease (hemizygotes) pass the defective gene on to all of their daughters and none of their sons. Females (heterozygotes) have a 50% chance of passing on the defective gene to each of their offspring, regardless of gender. Virtually all males with the defective gene are subject to substantial morbidity and mortality.12 Females with the defective gene may demonstrate a wide range of disease severity due to variability of the X-chromosomal inactivation within cells; they may be asymptomatic in some cases. The rates of progression of organ impairment may be slower in females than in males with Fabry disease. However, potentially life-threatening complications can develop in a specific organ, even in females whose presentation suggests a more moderate disease course.

The defects in the α-GAL gene are heterogeneous, and most families have private mutations.12,13 The wide range of mutations may explain variations in clinical presentation; therefore, efforts to establish phenotype/genotype correlations have been limited.1,3,15

 

Indication and Usage

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

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. In clinical trials and postmarketing safety experience, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids. If severe allergic or anaphylactic reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

  • In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.
  • Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.
  • If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
  • If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.
  • Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated.
  • Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

Re-administration of Fabrazyme to patients who have previously experienced severe or serious allergic reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel and with appropriate medical support measures readily available.

The most common adverse reactions reported are infusion reactions, some of which were severe. Infusion reactions occurred in approximately 50-55% of patients during Fabrazyme administration in clinical trials. Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, fever, 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.

  • Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.
  • Other serious adverse events reported in clinical studies 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.
  • Severe and serious infusion related reactions have been reported in postmarketing experience, some of which were life threatening including anaphylactic shock. In addition to the above adverse reactions, the following have been reported during postmarketing use of Fabrazyme: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased and hypoxia.
  • Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.

The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients.

In clinical trials, 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 antibodies.

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. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A Deficiency: Fabry Disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G eds. OMMBID - The Online Metabolic and Molecular Bases of Inherited Diseases. New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=474&Sectionid=45374153. Accessed September 04, 2014.
  2. Peters FPJ, Vermeulen A, Kho TL. Anderson-Fabry’s disease: alpha galactosidase deficiency. Lancet 2001;357:138-40.
  3. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249-54.
  4. Wang RY, Lelis A, Mirocha J, et al. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007:9(1):34–45.
  5. Wendrich K, Whybra C, Ries M, Gal A, Beck M. Neurological manifestation of Fabry disease in females. Contrib Nephrol 2001;136:241-4.
  6. Whybra C, Kampmann I, Willers J, et al. Anderson-Fabry disease: Clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 2001;24:715-724.
  7. Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: A cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine 2005;84:261-268.
  8. Baehner F, Kampmann C, Whybra E, et al. Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study. J Inherit Metab Dis 2003;26:617-627.
  9. Fellgiebel A, Muller MJ, Mazanek M, et al. White matter lesion severity in male and female patients with Fabry disease. Neurology 2005;65:600-602.
  10. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol Genet Metab 2008; 93:112-128.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.
  16. 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.

Fabry Fact

Kidney damage can begin early with glomerular and vascular changes present before progression to overt proteinuria and decreased glomerular filtration rate.