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 altered 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 Females

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

Warnings and Precautions
Anaphylaxis and Allergic Reactions: 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.

Infusion-Associated Reactions: In clinical trials with Fabrazyme, 59% of patients experienced infusion-associated reactions, some of which were severe.

  • In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment.
  • If an infusion-associated 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-associated 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-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

Compromised Cardiac Function: Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion-associated reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.

Immunogenicity and Rechallenge: 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. 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.

Adverse Reactions

  • Common adverse reactions reported (≥20% and >2.5% compared to placebo) were upper respiratory tract infection (44% vs 30%), headache (39% vs 28%), cough (33% vs 25%), paresthesia (31% vs 18%), fatigue (24% vs 17%), dizziness (21% vs 8%), peripheral edema (21% vs 7%), and rash (20% vs 10%).
  • Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions based on a pooled analysis of 150 patients treated with Fabrazyme in double-blind and open-label clinical studies 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.
  • Other serious adverse events reported in clinical studies included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, 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.
  • 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 of Fabrazyme in patients younger than 8 years of age have not been evaluated.

Please see full prescribing information for Fabrazyme.


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