Fabry Disease in Children

While hearing that the diagnosis is Fabry disease can be frightening for children and parents, it sometimes serves as validation and explanation of many of the symptoms they have been experiencing, sometimes for years.

The early signs and symptoms of Fabry disease are often mistaken for other, more common disorders. Recent research shows that while boys experience a higher frequency of symptoms at an earlier age than girls,1 both sexes can experience considerable symptoms. GL-3 accumulation starts early in life and continues over decades.

An analysis of  352 untreated pediatric Fabry patients1 in the Fabry Registry found a wide range of signs and symptoms:

  • Median age at enrollment in the Fabry Registry was 12 years for both males and females. The median age at symptom onset was 6 years in males and 9 years in females.
  • Neurologic pain was often the first symptom (reported by 48.8% of children at enrollment) with a median age at onset at 8 years.
  • Gastrointestinal symptoms were reported by 27% of children with a median age at onset of 5 years in males and 9.5 years in females.
  • Males age 14-<18 years reported substantially impaired quality of life (QOL), as measured with the SF-36® health survey and females reported moderately impaired QOL.
  • Among males, height and weight were below the US 50th percentile (median 25th centile p=0.005 and p=0.003, respectively) for males.
  • Height and weight were > 50th centile for females (median 75th centile p=0.014 and p=0.0001, respectively).
  • Among both males and females, estimated GFR was substantially higher than the mean eGFR in healthy children. The elevated eGFR levels did not correlate with patients’ height, weight, or BMI.

The analysis also found evidence of serious symptom onset, including:

  • Brief Pain Inventory scores indicated that 53% of males and 15% of females had experienced moderate or severe pain during the previous 24 hours. Most had not received treatment for pain.
  • Cardiac abnormalities were present in both boys and girls, including 9 children with arrhythmias and 3 children with left ventricular hypertrophy.
  • Three pediatric patients exhibited overt renal disease (i.e., stage 2 or 3 CKD) and 13 patients exhibited proteinuria or microalbuminuria, indicating some level of renal dysfunction.
  • Mean and median eGFR values were >140 ml/min/1.73m2 among both genders and 22% of those with available data exhibited eGFR >170 ml/min/1.73m2, suggesting possible renal hyperfiltration.

While some pediatricians may never see a patient with Fabry disease, others will see many—where there is one patient, there are often other family members affected by the disorder.

Early signs and symptoms of Fabry disease have been mistaken for growing pains, malingering, or psychosomatic problems.2 By recognizing the signs and symptoms of Fabry disease, physicians have the opportunity to identify Fabry disease earlier in the disease course, and to initiate the appropriate interventions. Perhaps as important, the diagnosis of one patient makes earlier diagnosis possible for affected family members.

The safety and effectiveness of Fabrazyme in patients younger than 8 years of age have not been studied.

Fabrazyme has been shown to reduce globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

If you suspect Fabry disease in a patient, a geneticist can help provide a definitive diagnosis. Learn more about Diagnosing Fabry Disease.

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.

References

  1. Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, Lemay R, Tylki-Szymanska A, Wilcox WR. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatric Research 2008 64:550-555.
  2. 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.