Genetics of Fabry Disease Treatment & Management

Updated: Aug 23, 2018
  • Author: Robert J Desnick, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Treatment

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.

Enzyme replacement therapy (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). [7] 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. [8]

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.

A literature review by Spada et al indicated that in pediatric patients with Fabry disease, ERT can significantly diminish plasma and urine levels of GL-3, relieve pain, and improve gastrointestinal symptoms and quality of life. The investigators reported that agalsidase’s impact on GL-3 clearance from podocytes seems to be dose dependent. [9]

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. [10]

Alpha-galactosidase A stabilizers

In August 2018, the US Food and Drug Administration (FDA) approved migalastat (Galafold) for the treatment of adults in whom a diagnosis of Fabry disease has been confirmed and who possess an amenable galactosidase-α gene (GLA) variant (as determined through in vitro assay data). Binding to and stabilizing endogenous α-galactosidase A (α-Gal A), migalastat chaperones the enzyme from the endoplasmic reticulum to lysosomes, where α-Gal A can degrade the accumulated glycolipid (globotriaosylceramide [GL-3]) and globotriaosylsphingosine (lyso-Gb3).

The efficacy of migalastat therapy is supported by the FACETS and ATTRACT clinical trials. The FACETS trial showed that after 6 months, the improvement rate for diarrhea was significantly greater in Fabry disease patients with an amenable mutation who received migalastat than in those treated with placebo (43% vs 11%). [11]

Results from the ATTRACT trial revealed the impact on renal function by migalastat and ERT to be similar. In addition, patients on migalastat showed a significant decrease in the left ventricular mass index (-6.6 g/m2), while those treated with ERT demonstrated no significant index change. Twenty-nine percent of migalastat patients experienced renal, cardiac, or cerebrovascular events during 18 months of treatment, compared with 44% in the ERT group. When patients were switched from ERT to migalastat, plasma globotriaosylsphingosine levels remained low and stable. [12]

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.

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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.

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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

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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.

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