Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Genetics of Fabry Disease Treatment & Management

  • Author: Robert J Desnick, MD, PhD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Feb 24, 2016
 

Medical Care

Fabry disease management strategies should be tailored to the individual according to patient age and disease stage. These strategies include the use of medication to alleviate the symptoms, disease-specific treatment to delay and prevent possible serious organ damage, and adherence to standard health care measures and a healthy lifestyle.

Pain management

Daily prophylactic doses of neuropathic pain agents (eg, phenytoin, carbamazepine, gabapentin, or a combination of these agents) provide some degree of relief. They are effective in decreasing the frequency and severity of pain episodes or pain crises in most patients.

Some patients may require more potent analgesics (eg, opioids) for pain management.

Management of GI symptoms

No specific treatment has been found to control GI symptoms in Fabry disease. However, pancrelipase, metoclopramide, H2 blockers, loperamide, and hydrochloride can ameliorate GI symptoms in some patients.

Patients with abdominal symptoms often benefit from a change in eating habits that includes frequent small meals.

Management of skin symptoms

The results of various laser methods used to treat angiokeratomas in patients with Fabry disease have not been promising for patients who are not receiving enzyme replacement therapy (ERT).

Lesions that are more pedunculated may be treated with a series of liquid nitrogen treatments prior to laser therapy.

Management of visual symptoms

Ocular symptoms in patients with Fabry disease rarely, if ever, cause significant impairment of vision and, as a rule, do not require treatment.

Management of other symptoms

Symptomatic treatment of renal, cardiovascular, and cerebrovascular complications is warranted.

ERT

ERT provides the patient with the biologically functional protein. The infused enzyme is taken up into lysosomes through specific receptors located on the surface of the target cells. Reversal of the metabolic and pathologic abnormalities in the cells and tissues are the key therapeutic goals of ERT. These changes should, in turn, result in improvement of symptoms and prevention of disease complications.

Multiple clinical trials with recombinant α -Gal A (agalsidase β [Fabrazyme]: Genzyme Corporation, Cambridge, Mass; agalsidase alfa [Replagal]: TKT Corporation, Cambridge, Mass) have been performed to investigate the safety and efficacy of ERT in patients with Fabry disease. The outcomes of these clinical studies were the basis for approval of Fabrazyme and Replagal in most European countries in 2001 and for the approval of Fabrazyme in the United States in 2003. The enzyme is administered intravenously. Replagal is intravenously administered at a dose of 0.2 mg/kg every 2 weeks, and Fabrazyme is intravenously administered at a dose of 1 mg/kg every 2 weeks.

West et al summarized the effects of agalsidase alfa on kidney function from 3 prospective, randomized, placebo-controlled trials (n=108).[5] Treatment with agalsidase alfa did not affect proteinuria and glomerular filtration rate (GFR) category at baseline was predictive of the rate of GFR decline. Patients treated with agalsidase had a lower annualized rate of GFR decline compared with those in the placebo group. These data represent the largest group of patients with Fabry disease taking enzyme replacement therapy evaluated for effects on kidney function. Agalsidase may help stabilize kidney function in Fabry disease.[6]

Initial clinical studies with recombinant α -Gal A showed that ERT is safe and well tolerated, except for mild-to-moderate infusion–associated reactions, which have been managed conservatively. During the phase 3 clinical study, Fabrazyme was shown to clear GL-3 from the plasma and capillary endothelium of the major sites of pathology, such as the kidney, heart, and skin.

The clinical benefits of ERT using α -Gal A in patients with advanced Fabry disease were examined in a phase 4 clinical study, which had a double-blind, placebo-controlled design. The rate of progression of renal, cardiac, and cerebrovascular complications and death among patients who received active drug was reduced compared with the placebo group. Therefore, starting ERT immediately after diagnosis to prevent irreversible organ damage is reasonable.

The commercial availability of Replagal and Fabrazyme has allowed treatment for many patients around the world. This increased use has enabled further assessment of the effect of ERT on various clinical manifestations of Fabry disease. A growing body of evidence suggests that ERT is beneficial in improving most disease symptoms. However, the response to ERT may vary, depending in part on tissue-specific differences in drug delivery and disease stage. A summary of the effect of ERT on various manifestations as reported by the authors and others is as follows:

  • Improved acroparesthesias
  • Improved GI symptoms
  • Improvement of hypohidrosis and anhidrosis
  • Improvement in the function of C-, –Ad-, and Ab-nerve fibers
  • Stabilization of deteriorating renal function
  • Improved cardiac function
  • Improved lymphedema
  • Improved vertigo
  • Stabilization and occasional improvement in hearing
  • Reduction in stroke frequency

Current recommendations suggest that ERT should be initiated as early as possible in all males with Fabry disease (including those with end-stage renal disease). Symptomatic female carriers with serious organ system involvement should also be assessed for ERT administration.

The following signs and symptoms suggest serious implications of Fabry disease in females that warrant ERT:

  • Uncontrolled pain at any age that requires alteration of lifestyle and interferes with quality of life
  • Presence of and a progressive increase in proteinuria, exceeding 300 mg per 24 hours or renal biopsy findings that suggest significant renal involvement
  • Patients on dialysis or who have undergone transplantation
  • Ischemic heart disease with or without cardiac dysfunction
  • Moderate-to-severe heart enlargement (ie, LVH)
  • Heart rhythm abnormalities
  • Significant brain involvement or MRI changes
  • Frequent severe vertigo episodes
  • Severe fatigue

A study by Trimarchi et al found that patients with Fabry disease who were undergoing enzyme therapy exhibited significantly lower podocyturia than did Fabry disease patients who were not being treated, although it was also found that the untreated patients displayed lower proteinuria and better renal function than did the treated patients. The investigators suggested that podocyturia precedes the development of proteinuria in Fabry disease and that enzyme therapy discourages podocyte loss.[7]

Adjunctive therapies and preventive measures

Use of ACE inhibitors and/or blockers in patients with proteinuria is the criterion standard. The dose should be optimized by a nephrologist.

Control of hypertension is essential.

Dyslipidemia (most commonly, hypercholesterolemia) should be treated.

Prophylaxis with antiplatelet or anticoagulant medication can be important in patients who have had transient ischemic attacks or a stroke.

Permanent cardiac pacing should be considered in high-risk patients.

Hearing loss can be treated with hearing aids. Patients should avoid excessive noise exposure.

Patients should be encouraged to maintain a healthy lifestyle, such as avoiding smoking.

Next

Surgical Care

In patients who have undergone renal transplantation, engrafted kidneys from unaffected and noncarrier individuals correct kidney function and remain free of GL-3 storage because the transplanted kidney is capable of producing normal levels of α -Gal A. However, other organ system damage continues unabated in patients who have undergone kidney transplantation.

In particular, vascular disease of the heart and brain may continue to progress. Thus, these patients should receive or continue to receive ERT.

Previous
Next

Consultations

A multidisciplinary team is essential. Emotional support and family counseling should be an integral part of patient care. In addition, providing patients with the resources to learn about Fabry disease and to contact other patients and families struggling with similar issues may help ameliorate feelings of isolation. Consultations should include the following:

  • Medical geneticist
  • Nephrologist
  • Cardiologist
  • Ophthalmologist
  • Pain specialist
  • Neurologist
Previous
Next

Diet

A "renal diet" is recommended for patients with proteinuria and renal failure.

A nutritionist should supervise a low-protein and low-sodium diet.

Patients are advised to monitor their activity level in order to avoid factors that precipitate symptoms. For example, adequate hydration prior to any physical activity and avoidance of exposure to extreme temperatures are recommended to avoid pain.

Previous
 
 
Contributor Information and Disclosures
Author

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 Society for Biochemistry and Molecular Biology, Eastern Society for Pediatric Research, American College of Medical Genetics and Genomics, American Pediatric Society, American Society for Clinical Investigation, American Society for Microbiology, American Society of Human Genetics, Central Society for Clinical and Translational Research, New York Academy of Sciences, Sigma Xi, Society for Experimental Biology and Medicine, Society for Pediatric Research

Disclosure: Received consulting fee from Amicus Therapeutics for consulting; Received consulting fee from Genzyme for consulting; Received grant/research funds from Genzyme for consulting; Received royalty from Genzyme for none; Received scientific advisory board from Genzyme for none; Received consulting fee from Synageva BioPharma for none; Received stock options from Synageva BioPharma for none; Received royalty from Shire HGT for none.

Coauthor(s)

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.

Maryam Banikazemi, MD Assistant Professor of Clinical Pediatrics, New York Medical College

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

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 and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

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, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

References
  1. Watanabe H, Goto S, Miyashita A, et al. Role of the p.E66Q variant of GLA in the progression of chronic kidney disease. Clin Exp Nephrol. 2014 Apr 10. [Medline].

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

  3. [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. 2003 Feb 18. 138(4):338-46. [Medline]. [Full Text].

  4. 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. 2012 Mar 20. 84(6):2745-53. [Medline].

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

  6. 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. 2012 Mar. 105(3):443-9. [Medline].

  7. Trimarchi H, Canzonieri R, Schiel A, et al. Podocyturia is significantly elevated in untreated vs treated Fabry adult patients. J Nephrol. 2016 Feb 3. [Medline].

  8. 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. 2000 Jul. 48(4):227-35. [Medline].

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

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

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

  12. 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. 2002 Apr. 11(2):121-46. [Medline].

  13. 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. 1986 Jul. 83(13):4859-63. [Medline]. [Full Text].

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

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

  16. 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. 2012 Mar 19. [Medline].

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

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

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

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

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

  22. 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. 2001 Mar. 68(3):711-22. [Medline]. [Full Text].

  23. 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. 2001 Jul 5. 345(1):9-16. [Medline].

  24. 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. 1998 May. 30(3):842-3. [Medline].

  25. 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. 2001 Jul 5. 345(1):25-32. [Medline].

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

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

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

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

  30. 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. 1990 May. 75(277):491-507. [Medline].

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

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

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

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

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

  36. 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. 2000 Jan 4. 97(1):365-70. [Medline]. [Full Text].

  37. 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. 1991 Feb 7. 324(6):395-9. [Medline].

  38. 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. 2004 Jul. 75(1):65-74. [Medline]. [Full Text].

 
Previous
Next
 
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.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.