Fabry Disease in Males and Females

Fabry disease is an X-linked inherited disorder that was once thought to affect only males, with females generally considered to be carriers.

Recent research shows that most females who carry the gene for Fabry disease develop symptoms.1-4 Fabry disease symptoms are more variable in females than they are in males, and may affect fewer organ systems. However, potentially life-threatening complications can develop in a specific organ, even in females whose presentation suggests a more moderate disease course.

The variable expression of Fabry disease in females is thought to be influenced by X-inactivation, a phenomenon in which one of two haploid sets of X-linked genes in each cell is inactivated, apparently at random, and has no phenotypic expression. X-inactivation should statistically result in 50 percent of mutated genes being inactivated in females. However, the incidence of severe skewing, or non-random inactivation (defined as a ratio of 90:10 or more), is relatively common.5 The pattern of inactivation may differ from one organ to another, so that a female patient may experience severe Fabry symptoms in some organ systems while remaining symptom-free in others.6

Analysis has shown that X-inactivation is an important factor in determining the severity of clinical involvement in heterozygous females, and that there is a statistically significant difference between the symptom severity scores of patients with balanced and skewed X-inactivation patterns.7

Cardiac Manifestations

  • Data from the Fabry Registry reported that 10% of females (n = 106) and 12.8% of males (n = 145) presented with cardiac manifestations at median ages of 33.4 and 21.6, respectively.8 Cardiac manifestations included myocardial infarction, significant cardiac procedures, arrhythmia, angina pectoris, congestive heart failure, and left ventricular hypertrophy.
  • A prospective study of cardiac manifestations in 55 females diagnosed with Fabry disease found a strong correlation between left ventricular hypertrophy (LVH) and age (r=0.905; p<0.0001). The mean patient age was 39.6 (range 6.1 to 70.8 years). All 25 of the women over age 45 had LVH.9
  • In a study of 34 consecutive women diagnosed with late-onset hypertrophic cardiomyopathy, four (12%) carried the defective α-GAL gene. In each of these women, the heart was the only clinically affected organ.10
  • In a study of 129 Fabry disease patients (80 females and 49 males) 39% of females (n = 31) and 30% of males (n = 15) were affected by right ventricular hypertrophy.11
  • In a European outcomes database known as the Fabry Outcome Survey that included 366 Fabry disease patients (201 males and 165 females), cardiac symptoms including angina, arrhythmias, and dyspnea, were reported in 69% of males and 65% of females. LVH was observed in 46% of males and 28% of females, with an average age of onset of 38.0 and 55.4 years, respectively.5

Cerebrovascular Manifestations

  • Data from the Fabry Registry reported that 4.2% of females (n = 44) and 6.7% of males (n = 76) reported experiencing a stroke at median ages of 43.8 and 39.5, respectively.8 In addition, 3.9% of females (n = 41) and 1.7% of males (n = 19) reported experiencing transient ischemic attack.1
  • Cerebrovascular events were reported to be more likely in females than males, with 27% of 165 females and 12% of 201 males in the European outcomes database experiencing stroke, transient ischemic attack, or prolonged reversible ischemic neurologic deficit.5
  • A study of white matter lesion severity in 13 males and 14 females with Fabry disease found a comparable incidence (36% of females and 31% of males) and level of severity in both groups.12

Renal Manifestations

  • According to Fabry Registry data, many female patients were reported to exhibit significant kidney involvement as manifested by proteinuria and reduced eGFR. Among the 1,055 females, 23 (2.2%) had reached ESRD, requiring dialysis or transplantation at a mean age of 39.2 years (range 17–77 years). Among males, 156 (13.8%) had reached ESRD at a similar mean age, 38.2 years (range 14–79 years). Compared to males, a lower percentage of female patients exhibited renal manifestations across all categories. However, among females who did exhibit renal manifestations, the mean age at which these were reported was similar or only slightly higher than what was reported for male patients.8
  • In the European outcomes database, proteinuria was observed in 33% of females vs. 44% of males, and end-stage renal failure was present in 1% of females and 17% of males aged greater than 18 years.5

Neurological Manifestations

  • Neurological symptoms have been the most frequently reported symptoms in both males and females.8
  • In an analysis of Fabry Registry data, 457 females (43.3%) and 716 males (63.3%) of males reported experiencing pain beginning at ages 14.2 and 10.4, respectively.8

Gastrointestinal Manifestations

  • Initial symptoms that were gastrointestinal in nature were reported by 209 males (18.5%) and 126 females (11.9%) in the Fabry Registry, with an average age of onset of 10.8 ± 9.6 years in males and 18.7 ± 13.4 years in females. However, when data from clinical follow-up assessments were combined with enrollment medical history data, a higher percentage of female patients reported abdominal pain and diarrhea, as compared to males. Among females, 226 (21.4%) reported abdominal pain and 199 (18.9%) reported diarrhea; whereas abdominal pain and diarrhea were reported by 152 (13.4%) and 135 (11.9%) male patients.8

Dermatologic Manifestations

  • In the European outcomes database, dermatologic symptoms were reported in 78% of males and 50% of females, and angiokeratomas were reported present from a mean age of 17.9 in males and 29.1 years in females.5
  • In the Fabry Registry, skin symptoms were reported in 118 females (11.2%) and 359 males (31.7%).8

Ophthalmologic Manifestations

  • Corneal verticillata, visible only with slit lamp ophthalmoscopy, are nearly universal in males and have been reported in 70% of females.13

Quality of Life

  • According to Fabry Registry data, quality of life, as measured by the SF-36 survey, was impaired at a later age in females than in males, but both genders experienced significantly impaired QoL from the third decade of life onward.8

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. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol Genet Metab 2007; doi:10.1016/ j.ymgme. 2007.09.013.
  2. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007;9:34-45.
  3. Whybra C, Kampmann I, Willers J, et al. Anderson-Fabry disease: Clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 2001;24:715-724.
  4. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769-775.
  5. Mehta A, Ricci R, Widener U, et al. Fabry disease defined: Baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Euro J Clin Invest 2004:34;236-242.
  6. Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, et al. Uneven X-inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the α-galactosidase A gene. J Med Genet 1996;33:682-688.
  7. Dobrovolny R, Dvorakova L, Ledvinova J, et al. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J Mol Med 2005;83:647-654.
  8. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol Genet Metab 2008; 93:112-128.
  9. Kampmann C, Baehner F, Whybra C, et al. Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol 2002;40:1668-1674. 2004;110:1047-1053.
  10. Chimenti et al. Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110:1047-1053.
  11. Kampmann C, Baehner FA, Whybra C, et al. The right ventricle in Fabry disease. Act Paediatrica 2005;94(Suppl 447):15-18.
  12. Fellgiebel A, Muller MJ, Mazanek M, et al. White matter lesion severity in male and female patients with Fabry disease. Neurology 2005;65:600-602.
  13. Desnick R, Brady R. Fabry disease in childhood. J Pediatr 2004;144:S20-6.