Diagnosing Fabry Disease

Hemizygous Males

Clinical diagnosis of Fabry disease in males is based on family history, history of childhood fevers in association with pain in the extremities, and, where present, the characteristic skin lesions (angiokeratomas), “whorled” corneal opacity, and the presence of lipid-laden cells in urinary sediment or biopsied tissues.

Diagnosis is confirmed biochemically by very low or undetectable α-GAL activity 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 (α-galactosidase B) activity.1 (See Diagnostic Testing for information about diagnostic laboratories).

Although 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.2,3 Delayed diagnosis may be due to under-recognition of the disease. In addition, Fabry disease symptoms have been diagnosed as 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.3-8

Given the progressive nature of Fabry disease, early diagnosis is important. Once a diagnosis is made, a medical family pedigree can be obtained and families can be directed to diagnostic, therapeutic, and support services, including genetic counseling. Because the disease is genetic, a family tree makes it possible to predict who is at risk for inheriting the defective gene.

Hemizygotes who are suspected to be atypical variants can be identified by low α-GAL activity.4,9 These patients may be diagnosed after the onset of cardiac or renal manifestations. They generally do not exhibit earlier signs and symptoms.

Heterozygotes

The majority of heterozygotes (with or without manifestations) have below normal levels of α-GAL activity and the characteristic “whorled” corneal opacity.4 However, absence of these clinical indicators does not preclude Fabry diagnosis. Potentially life-threatening complications can develop in a specific organ, even in females whose presentation suggests a more moderate disease course.

In Fabry kindreds with a known mutation, mutation analysis can identify heterozygotes. In families for whom a specific mutation is not documented, linkage analysis can be performed.10

Prenatal Diagnosis

Hemizygotes can be identified prenatally 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).4 Heterozygotes can be identified prenatally if the family mutation is known.

Patients younger than 8 years of age were not included in clinical studies of Fabrazyme. The safety and efficacy in patients younger than 8 years of age have not been evaluated.

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. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1‑800‑FDA‑1088. You may also contact Sanofi Genzyme at 1-800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Sanofi Genzyme at 1-800-745-4447.

References

  1. 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.
  2. 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.
  3. Morgan SH, Crawfurd MA. Anderson-Fabry disease. BMJ 1988;297:872-3.
  4. 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.
  5. Elleder M, Poupe˘tová H, Kozich V. Fetální patologie Fabryho nemoci a mukopolysacharidózy I. Cesk Patol 1998;1:7-12.
  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. Kolodny EH. Fabry disease. In: Bogousslavsky J, Caplan L, eds. Stroke Syndromes. New York: Cambridge University Press 1995;453-9.
  8. Stryker VL, Kreps C. Fabry disease. Am J Nurs 2001;101:39-44.
  9. 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, New Orleans; March 14-17, 2002.
  10. 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;71:329-35.