Genetics of Fabry Disease Workup

  • Author: Maryam Banikazemi, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 27, 2012
 

Laboratory Studies

The following studies are indicated in Fabry disease:

α -Gal A

α -Gal A activity may be measured in plasma, serum, and leukocytes. Tissue biopsies and cultured skin fibroblasts may also be used to measure a -Gal A activity.

In males with the classic or variant phenotype, the disease is readily diagnosed based on low α -Gal A activity.

Female carriers may have α -Gal A activity that ranges from zero to within the reference range. Thus, enzyme assays are rarely helpful in determining female carrier status.

DNA analysis

DNA isolated from blood or biopsy specimens can be used for analysis of the α -Gal A gene sequence to identify the disease-causing mutation. DNA testing is the preferred method for identifying and confirming the carrier status of females in whom enzyme activity is within or near the reference range.

Laboratory tests after diagnosis

After the diagnosis has been confirmed using enzyme assays, DNA testing, or both, carefully assess the patient. A recommended minimum assessment schedule has been developed by the Fabry Board of Advisors[1] and other experts in the field.[2] The recommended assessment frequency depends on patient age and previous findings. Females and males should undergo the same degree of assessment and monitoring. The following recommended laboratory assessments should be obtained at baseline and at appropriate intervals:

CBC count, serum electrolyte level measurement, and lipid profile

Obtain at baseline and appropriate intervals.

Renal evaluation

Serum BUN and creatinine levels and 24-hour urine or spot urine measurement for total protein/creatinine, albumin/creatinine, sodium, creatinine, and urinary GL-3 (optional) levels.[3]

Renal biopsy (This may be warranted in atypical cases to exclude any other causes of renal disease.)

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Imaging Studies

CNS evaluation

MRI is used to document evidence of brain ischemic disease.

Magnetic resonance angiography (MRA) may be indicated to assess cerebral vasculopathy.

Peripheral nerves should be periodically assessed using a detailed neurological examination.

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Other Tests

Cardiac evaluation

Ventricular hypertrophy and septal thickening can be demonstrated using echocardiography. If left ventricular hypertrophy (LVH) is present, a cardiac MRI with contrast can be performed to evaluate the presence of scarring.

Abnormal ECG findings include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval. Evidence of LVH and previous ischemic injury may also be present.

Holter monitoring in selected patients may provide important information.

Psychosocial evaluation

All health care professionals who treat patients with Fabry disease should be sensitive to the psychosocial burden of a chronic, rare, and progressive disease. In these families, denial, guilt, and anger frequently play a significant role in intrafamilial dynamics. Pay special attention to the history and signs of anxiety disorders, clinical depression, suicidal ideation or attempts, and substance abuse.

Pulmonary evaluation

Perform induced sputum analysis, lung biopsy, or both if severe pulmonary involvement is present (to exclude an intercurrent disease process).

Visual evaluation

Perform slit-lamp microscopy to identify the typical Fabry disease–specific changes in the cornea, lens, retina, and conjunctiva.

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Contributor Information and Disclosures
Author

Maryam Banikazemi, MD  Assistant Professor of Clinical Pediatrics, Department of Clinical and Molecular Genetics, Columbia University College of Physicians and Surgeons; Director of Newborn Screening Program, Director of Lysosomal Storage Disorders Program, Department of Pediatrics, Columbia University Medical Center

Maryam Banikazemi, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Robert J Desnick, MD, PhD  Dean for Genetics and Genomics, Professor and Chairman, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine

Robert J Desnick, MD, PhD is a member of the following medical societies: American College of Medical Genetics, American Pediatric Society, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society for Microbiology, American Society of Human Genetics, Central Society for Clinical Research, Eastern Society for Pediatric Research, New York Academy of Sciences, Sigma Xi, Society for Experimental Biology and Medicine, and Society for Pediatric Research

Disclosure: Amicus Therapeutics Consulting fee Consulting; Genzyme Consulting fee Consulting; Synageva BioPharma Consulting fee Consulting

Kenneth H Astrin, PhD  Associate Professor of Human Genetics, Department of Human Genetics, Mount Sinai School of Medicine

Kenneth H Astrin, PhD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. [Guideline] Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. Sep 2006;8(9):539-48. [Medline].

  2. [Guideline] Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. Feb 18 2003;138(4):338-46. [Medline]. [Full Text].

  3. Auray-Blais C, Boutin M, Gagnon R, Dupont FO, Lavoie P, Clarke JT. Urinary globotriaosylsphingosine-related biomarkers for fabry disease targeted by metabolomics. Anal Chem. Mar 20 2012;84(6):2745-53. [Medline].

  4. [Best Evidence] West M, Nicholls K, Mehta A, et al. Agalsidase alfa and kidney dysfunction in Fabry disease. J Am Soc Nephrol. May 2009;20(5):1132-9. [Medline].

  5. Wilcox WR, Linthorst GE, Germain DP, Feldt-Rasmussen U, Waldek S, Richards SM, et al. Anti-a-galactosidase A antibody response to agalsidase beta treatment: Data from the Fabry Registry. Mol Genet Metab. Mar 2012;105(3):443-9. [Medline].

  6. Ashton-Prolla P, Tong B, Shabbeer J, et al. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med. Jul 2000;48(4):227-35. [Medline].

  7. [Best Evidence] Banikazemi M, Bultas J, Waldek S, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. Jan 16 2007;146(2):77-86. [Medline]. [Full Text].

  8. Banikazemi M, Desnick RJ. Does enzyme replacement therapy improve symptoms of Fabry disease in patients undergoing dialysis?. Nat Clin Pract Nephrol. Feb 2006;2(2):72-3. [Medline].

  9. Banikazemi M, Ullman T, Desnick RJ. Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab. Aug 2005;85(4):255-9. [Medline].

  10. Bennett RL, Hart KA, O'Rourke E, et al. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors. J Genet Couns. Apr 2002;11(2):121-46. [Medline].

  11. Bishop DF, Calhoun DH, Bernstein HS, et al. Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci U S A. Jul 1986;83(13):4859-63. [Medline]. [Full Text].

  12. Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA. Dec 6 2000;284(21):2771-5. [Medline].

  13. Bühler FR, Thiel G, Dubach UC, Enderlin F, Gloor F, Tholen H. Kidney transplantation in Fabry's disease. Br Med J. Jul 7 1973;3(5870):28-9. [Medline].

  14. Chien YH, Lee NC, Chiang SC, Desnick RJ, Hwu WL. Fabry Disease: Incidence of the Common Later-Onset a -Galactosidase A IVS4+919G>A Mutation in Taiwanese Newborns -- Superiority of DNA-Based to Enzyme-Based Newborn Screening for Common Mutations. Mol Med. Mar 19 2012;[Medline].

  15. Cho ME, Kopp JB. Fabry disease in the era of enzyme replacement therapy: a renal perspective. Pediatr Nephrol. Jun 2004;19(6):583-93. [Medline].

  16. Colombi A, Kostyal A, Bracher R, Gloor F, Mazzi R, Tholen H. Angiokeratoma corporis diffusum--Fabry's disease. Helv Med Acta. Dec 1967;34(1):67-83. [Medline].

  17. Crutchfield KE, Patronas NJ, Dambrosia JM, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology. Jun 1998;50(6):1746-9. [Medline].

  18. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27(3):385-410. [Medline].

  19. Desnick RJ, Ioannou YA, Eng CM. a-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, eds. In: Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Professional; 2001:3733-74.

  20. Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, et al. A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet. Mar 2001;68(3):711-22. [Medline]. [Full Text].

  21. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease. N Engl J Med. Jul 5 2001;345(1):9-16. [Medline].

  22. Erten Y, Ozdemir FN, Demirhan B, et al. A case of Fabry's disease with normal kidney function at 10 years after successful renal transplantation. Transplant Proc. May 1998;30(3):842-3. [Medline].

  23. Frustaci A, Chimenti C, Ricci R, et al. Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med. Jul 5 2001;345(1):25-32. [Medline].

  24. Goldman ME, Cantor R, Schwartz MF, et al. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol. May 1986;7(5):1157-61. [Medline].

  25. Hilz MJ, Brys M, Marthol H. Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology. Apr 13 2004;62(7):1066-72. [Medline].

  26. Hilz MJ, Stemper B, Kolodny EH, et al. Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain. Feb 2000;84(2-3):361-5. [Medline].

  27. Linthorst GE, De Rie MA, Tjiam KH. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol. Mar 2004;150(3):575-7. [Medline].

  28. Morgan SH, Rudge P, Smith SJ, et al. The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients. Q J Med. May 1990;75(277):491-507. [Medline].

  29. Ojo A, Meier-Kriesche HU, Friedman G, et al. Excellent outcome of renal transplantation in patients with Fabry's disease. Transplantation. Jun 15 2000;69(11):2337-9. [Medline].

  30. Ries M, Clarke JT, Whybra C, et al. Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics. Sep 2006;118(3):924-32. [Medline].

  31. Schiffmann R. Enzyme replacement in Fabry disease: the essence is in the kidney. Ann Intern Med. Jan 16 2007;146(2):142-4. [Medline].

  32. Schiffmann R. Neuropathy and Fabry disease: pathogenesis and enzyme replacement therapy. Acta Neurol Belg. Jun 2006;106(2):61-5. [Medline].

  33. Schiffmann R, Kopp JB, Austin HA, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. Jun 6 2001;285(21):2743-9. [Medline].

  34. Schiffmann R, Murray GJ, Treco D, Daniel P, Sellos-Moura M, Myers M, et al. Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A. Jan 4 2000;97(1):365-70. [Medline]. [Full Text].

  35. von Scheidt W, Eng CM, Fitzmaurice TF, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med. Feb 7 1991;324(6):395-9. [Medline].

  36. Wilcox WR, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst GE, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. Jul 2004;75(1):65-74. [Medline]. [Full Text].

 
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Angiokeratoma is the small punctate reddish-to-bluish angiectases on the umbilicus.
Angiokeratomas are commonly observed as dense cluster of lesions on the flank and private areas.
Corneal verticillata, commonly seen in patients with Fabry disease, detectable by slit lamp examination.
 
 
 
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