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.

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. 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.