Signs and Symptoms

^Presentation

The age of presentation, presenting symptoms and the clinical course of Fabry disease varies from individual to individual. However, patients with Fabry can be divided into three general groups: patients with classical Fabry disease, females with attenuated clinical manifestations, and atypical variants. Of these three categories, classical Fabry disease is the most extensively studied and the best understood. In general, the severity of Fabry disease correlates inversely with enzyme activity.

The cardinal presenting features are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas (Figure 1), hypohidrosis, heat/cold intolerance, and a characteristic “whorled” corneal opacity (Figure 3) that generally does not affect vision. In these patients, the major causes of mortality include renal failure, cardiomyopathy, and cerebrovascular accidents. Clinical onset usually begins in childhood, but signs and symptoms are similar to those associated with other more common disorders, which can delay diagnosis. ^[1]

Atypical variants are hemizygotes who have few or none of the hallmark symptoms of classical Fabry disease and have residual plasma α-GAL levels (1 to 30% of normal). ^[3,4] These patients present much later in life than patients with classical Fabry disease, and have manifestations predominately in one organ system. This patient category has only recently been recognized; therefore, little data regarding incidence and pathophysiology are available. Studies suggest that atypical Fabry disease may be more common than previously suspected. ^[3,5,6] In a study of 230 unselected males with left ventricular hypertrophy, 3% were found to have low α-GAL activity (4-14% of normal). ^[3] In another study of 79 men with late onset hypertrophic cardiomyopathy, 6.3% had low α-GAL levels and were subsequently found to have α-GAL mutations. ^[5] A study of 1,903 males on hemodialysis who were randomly selected from 37,147 patients attending 512 different dialysis facilities across the U.S., revealed that approximately 1.6% had Fabry disease. ^[7]

It is important to recognize that although most patients with classical Fabry disease are male, females can also have classical Fabry disease. The majority of female heterozygotes (with or without manifestations) have below normal levels of α-GAL activity and the characteristic “whorled” corneal opacity (Figure 3).^[1] However, absence of these clinical indicators does not preclude Fabry carrier status, since some female heterozygotes have tissue-specific normal α-GAL activity. ^[1] In Fabry kindreds with a known mutation, mutation analysis can identify female heterozygotes. In families for whom a specific mutation is not documented, linkage analysis can be performed to establish carrier status. ^[8]

Below are symptoms listed by medical specialty that could indicate Fabry disease:

Pediatricians

Primary Care Providers

Nephrologists

Patients with Fabry disease may not be seen by a nephrologist until disease is advanced. In fact, a recent study found that approximately one in 100 male dialysis patients may have Fabry disease.^[2,7] Patients may present with the following:

• Proteinuria/isosthenuria
• Tubular dysfunction (polyuria, polydipsia)
• Symptoms suggesting Fanconi's syndrome (proximal tubular insufficiency, aminoaciduria, glycosuria, renal tubular acidosis)
• Elevated serum creatinine
• Progressive and/or unexplained renal insufficiency

Cardiologists

Gastroenterologists

Ophthalmologists

Dermatologists

Rheumatologists

Urologists

Neurologists

For more on differential diagnoses for Fabry disease, go to Diagnosis.

^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.

Indications 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, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-346.

2. Desnick RJ. Fabry disease: unrecognized ESRD patients and effectiveness of enzyme replacement on renal pathology and function. Am J Hum Genet; Suppl 71:417.

3. Nakao S, Takenaka T, Maeda M, Kodama C, Takana A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, Tanaka H. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 1995;333:288-93.

4. Nagao Y, Nakashima H, Fukuhara Y, Shimmoto M, Oshima A, Ikari Y, Mori Y, Sakuraba H, Suzuki Y. Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of α-galactosidase A. Clin Genet 1991;39:233-7.

5. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop D, Desnick RJ. An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-9.

6. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 2002;105:1407-11.

7. 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 to Annual Clinical Genetics Meeting. March 14, 2002; New Orleans, LA.

8. 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.