Fabry Disease

Fabry disease can be confirmed in males with deficiency of α‐gal A, most commonly measured in blood (leukocytes), and the presence of a disease causing mutation in the GLA gene located on Xq22.1. Although in the past low α‐gal A activity has been considered sufficient for diagnosis in males, the presence of a common pseudodeficiency allele, D313Y, that results in low plasma alpha‐gal A activity and slightly reduced leukocyte enzyme activity suggests that a diagnosis of Fabry disease should not be finalized until a disease causing GLA mutation is identified.

Measurement of α‐gal A enzyme activity is not reliable for diagnosis of Fabry in females because obligate heterozygotes have variable levels of α‐gal A that can overlap with enzyme levels found in healthy controls. In females confirmation of Fabry is via identification of a Fabry disease causing mutation in the GLA gene.

Biopsies of heart or kidney are not required for diagnosis in this condition, although storage patterns on biopsies may suggest a Fabry disease diagnosis in an affected individual.

Referrals by appropriate medical professionals to a metabolic specialist and genetic counselor for discussion of diagnosis, recurrence risk, construction of a detailed family history, identification of other at risk family members, and development of a comprehensive monitoring and treatment plan. Contact information for medical professionals experienced in treating Fabry disease patients can be found by contacting the National Fabry Disease Foundation.

Baseline evaluations to be ordered by and under the supervision of appropriate medical professionals as recommended for age group include:

• CBC, platelet count, serum creatinine and BUN, GL3, thyroid studies, common thrombophilic blood coagulation disorders, and a basic metabolic chemistry panel
• Routine urinalysis
• 24 h urine with creatinine, glomerular filtration rate, and protein clearance
• First morning urine measuring total protein and creatinine levels.
• EKG
• 24 h Holter monitor
• Echocardiogram and/or Cardiac Magnetic Resonance Imaging
• Brain Magnetic Resonance Imaging or Head CT
• Hearing examination
• Ophthalmologic examination
• Pulmonary function testing
• Depression/Anxiety assessment

Discussion with appropriate medical professionals of treatment with enzyme replacement therapy (ERT) treatment practices vary widely in recommended timing of beginning ERT, the decision to initiate therapy should be determined based on the clinical judgment of the managing metabolic specialist after reviewing baseline evaluations in conjunction with the patient or patient's family in affected minors.

Specific points to examine further during sessions include:

1. Ascertaining patients’ needs and concerns relating to a Fabry disease diagnosis
2. Identifying at‐risk family members through construction of a detailed pedigree and diagnostic testing,
3. Explaining the natural history and inheritance pattern of Fabry disease,
4. Provision of pre‐ and post‐ counseling regarding genetic testing including the issue of non‐paternity,
5. Navigation of personal and family testing (enzyme, sequencing, duplication/deletion testing),
6. Discussions related to prenatal testing and decision making, assessing the subjects’ psychosocial issues,
7. Identifying appropriate support resources.

Key Fabry‐specific points to address during these discussion topics include:

1. The X‐linked pattern of inheritance for Fabry disease and testing at‐risk family members. On average, there are five family members diagnosed with Fabry disease for every proband. Discussion should include issues of misattributed paternity which could arise from testing. This disease should be referred to as an X‐linked disorder not an “X‐linked recessive disorder.”
2. Clinical manifestations of Fabry disease occur in men and women. Women are not “just carriers”.
3. Fabry disease is progressive and often becomes symptomatic in childhood. The average presentation age in males is 6–8 years of age and 9 years of age in females, although age of symptom onset varies from individual to individual even within the same family. Nevertheless life threatening complications are rare in pediatric patients.
4. Types of genetic testing available and test limitations (e.g., enzyme assay can be normal in heterozygous females; the percentage of residual α‐gal‐A enzyme activity does not correlate with clinical severity; and mutations frequently cannot predict disease severity)
5. Issues related to genetic testing for Fabry disease such as testing “healthy” minors and insurance implications
6. Testing kidney donors, particularly family members, prior to transplant for Fabry disease.
7. Reproductive options including gamete donation, prenatal diagnosis and preimplantation diagnosis.
8. Teratogenic risk of frequently used medications in Fabry disease such as Dilantin, Carbamazepine (Tegretol), and ACE Inhibitors in pregnancy.
9. Issues related to treatment compliance on a life‐long infusion therapy including: transition from parent to patient directed medical care as the patient becomes an adult, insurance issues, realistic expectations of treatment efficacy, continued need for concomitant treatments and monitoring, and possible weight gain.
10. Identify potential substance abuse; pain can be one of the most debilitating features of Fabry disease, and there can be problems with substance abuse as a form of self‐medication.
11. Identify issues of sexuality. Men and women with Fabry disease may have concerns about body image, intimacy, and sexuality. For example, affected individuals may be embarrassed by angiokeratomas in their genital region. Chronic pain and fatigue and erectile dysfunction may also contribute to difficulties and problems with intimacy.
12. Review of management options and prevention, and referral to specialists as appropriate
13. Due to years of misdiagnosis, there can be an inherent mistrust of health professionals.
14. Discussion of the increased rate of depression, anxiety, and adaptive function disorders (ability to function in daily life and maintain relationships) seen in Fabry disease.
15. Discussion of the unique psychosocial issues in relation to Fabry disease. Overall the psychosocial issues in relation to a diagnosis of Fabry disease are similar to those associated with a diagnosis of other chronic genetic disorders (e.g., anxiety, anger, grief, denial, blame, hopelessness, and influence on self‐esteem and self‐identify, changed relationships with family of origin). The chronic nature of this condition can stress relationships. There is a higher rate of unemployment and suicide.