eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Fabry Disease: Treatment & Medication
Updated: Jul 8, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
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.
- 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).3 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.
- 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
- 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.
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 a -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.
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
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.
Medication
Analgesics
These agents are used to relieve neuropathic pain. Phenytoin and carbamazepine are 2 medications used to treat acroparesthesias in patients with Fabry disease. Either drug may be used, although some patients benefit from a combination.
Phenytoin (Dilantin)
Used for analgesia for acroparesthesia. May act in the motor cortex, where it may inhibit spread of seizure activity. Activity of the brainstem centers responsible for the tonic phase of grand mal seizures may also be inhibited. Individualize dose. Administer larger dose before bedtime if dose cannot be equally divided.
Adult
300 mg PO qd
Pediatric
100 mg PO qd
Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase phenytoin toxicity; effects of phenytoin may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, PO contraceptives, and valproic acid
Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Obtain CBC count and urinalyses when therapy is begun and at monthly intervals for several months to monitor for blood dyscrasias; discontinue if rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in patients with acute intermittent porphyria and diabetes (may elevate blood sugar levels); discontinue if hepatic dysfunction occurs
Carbamazepine (Tegretol)
Indicated for complex partial seizures and trigeminal neuralgia. May block posttetanic potentiation by reducing summation of temporal stimulation. May reduce polysynaptic responses and block posttetanic potentiation. Following therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once every 3 mo. Doses are typically lower than those used to treat seizures and are administered once daily.
Adult
300 mg PO qd
Pediatric
100 mg PO qd
Serum levels may increase significantly within 30 d of danazol coadministration (avoid when possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)
Documented hypersensitivity; bone marrow depression; administration of MAOIs within previous 14 d
Pregnancy
D - Unsafe in pregnancy
Precautions
Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum-iron baseline before treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness
Gabapentin (Neurontin)
FDA-approved PO medication for management of postherpetic neuralgia. Also FDA approved for the treatment of partial seizures in adults and children. Chemical structure similar to the inhibitory neurotransmitter GABA. Appears to work by raising GABA levels by some effect on a GABA transporter protein. Also decreases activity of voltage-gated calcium channels via binding to a secondary protein. Approved for epilepsy in children. Available as tab, cap, and liquid dosage forms.
Adult
100-300 mg PO qd initially; may slowly titrate upward as needed for pain; not to exceed 2400 mg/d
Pediatric
<3 years: Not established
3-12 years: Not established; limited data suggests 10-15 mg/kg/d PO divided q8h; may gradually titrate upward at 3-d intervals
>12 years: Administer as in adults
Antacids may significantly reduce bioavailability of gabapentin (administer at least 2 h following antacids); may significantly increase norethindrone levels ; cimetidine, hydrocodone, and morphine may increase gabapentin AUC; naproxen may increase gabapentin absorption
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include drowsiness, dizziness, somnolence, and unwanted eye movements; children may experience emotional ability hostility, thought disorder, and hyperkinesia; caution in elderly patients and those with severe renal impairment; abrupt withdrawal may precipitate seizures
Enzyme replacement therapy
a -Gal A deficiency leads to the accumulation of GSLs with terminal a -galactosyl residues. Clinical manifestations of Fabry disease are reflected in the tissue target sites of lipid storage. The recombinantly produced enzyme a -Gal A is available in Europe and United States.
Agalsidase (Fabrazyme, Replagal)
Recombinant form of the human enzyme a -Gal A, which is deficient in patients with Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduction or relief of neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells. Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.
Adult
Initial dose:
Fabrazyme: 1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk
Replagal: 0.2 mg/kg IV infused over 40 min q2wk
Maintenance dose: Not established
Pediatric
Not established; appropriate time to initiate treatment in children has not been determined
None reported
Documented hypersensitivity
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
May cause IgG antibody production (55% with Replagal, 83% with Fabrazyme); may cause allergic reactions (10% with Replagal, 59% with Fabrazyme), which are prevented by premedication with hydrocortisone and/or antihistamines (standard for Fabrazyme) before IV infusion; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment
More on Fabry Disease |
| Overview: Fabry Disease |
| Differential Diagnoses & Workup: Fabry Disease |
 Treatment & Medication: Fabry Disease |
| Follow-up: Fabry Disease |
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References
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Further Reading
Keywords
Fabry disease, Anderson-Fabry disease, Fabry's disease, α-galactosidase A deficiency, alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale, hereditary dystopic lipidosis, GLA deficiency, ceramide trihexosidase deficiency, error in metabolism, error of glycosphingolipid metabolism, stroke, acroparesthesias, hypohidrosis, angiokeratoma, renal failure, lysosomal storage disorder, enzyme replacement therapy, ERT, heart failure, myocardial infarction, left ventricular hypertrophy, LVH, valvular regurgitation, mitral valve prolapse, lymphedema, treatment, diagnosis
