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Angiokeratoma Corporis Diffusum (Fabry Syndrome): Treatment & Medication

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Anusuya Mokashi, MS, MD, Radiology Resident, Staten Island University Hospital; Arnold R Oppenheim, MD, Assistant Professor, Department of Internal Medicine, Division of Dermatology, Eastern Virginia School of Medicine
Contributor Information and Disclosures

Updated: Dec 21, 2009

Treatment

Medical Care

As a multisystemic disease, angiokeratoma corporis diffusum requires treatment by a number of specialists. Treatment is intended to extend the lifespan of affected patients and make their lives more comfortable, especially in light of the often excruciating pain they experience. Significant clinical improvement and enhancement of quality of life have been achieved with enzyme replacement therapy (ERT), in particular at the early stages of Fabry disease, with positive benefits for the cardiac and renal systems and a decrease in pain.

Early detection of Fabry disease has made extending the lifespan and improving the quality of life possible for these patients. The administration of recombinant human alpha-galactosidase or agalsidase beta replacement therapy can reverse and delay cardiac, renal, and neural damage to patients with Fabry disease. It is not clear which enzyme therapy is superior and both therapies are helpful at enhancing health.

Future treatments of Fabry disease that seem promising include (1) substrate deprivation based on the inhibition of an earlier step in the synthesis of the accumulating glycosphingolipid and (2) gene therapy.

  • Dermatology: Carbon dioxide laser treatment can improve cosmetic appearance by removing angiokeratomas from the skin. Variable pulse width 532-nm Nd:YAG laser therapy, 578-nm copper vapor laser therapy, and flashlamp-pumped dye laser therapy can also be used to treat angiokeratomas. Hyperhidrosis can be treated with topical and systemic antiperspirant agents. Hypohidrosis or anhidrosis can be treated with moisturizers and topical applications of artificial lacrimal fluid and saliva.
  • Nephrology: Renal insufficiency, the most common cause of mortality, can be treated with hemodialysis or kidney transplantation. Renal transplantation may benefit patients because it supplies a source of the missing enzyme alpha-galactosidase A.
  • Neurology: Two antiseizure medications, diphenylhydantoin and carbamazepine, are the most helpful in alleviating the debilitating pain of neurologic involvement.
  • Pulmonology: Obstructive lung disease is a problem late in the disease process. Discourage patients from smoking.
  • Gene therapy: In recent years, nucleoside sequencing of the entire alpha-galactosidase A gene has enabled theoretical treatment using recombinant technology.
  • Replacement therapy: Occasionally, infusions of plasma or partially purified enzyme from healthy donors have produced promising results.
  • Politei suggested that statins might be helpful in the treatment of Fabry disease to help prevent stroke, owing to neuroprotective properties or pleiotropic effects.25
  • In terms of cardiac care, Imbriaco et al reported that twice-monthly continuous treatment with agalsidase beta at 1 mg/kg every 2 weeks significantly reduced left ventricular hypertrophy, improving overall heart performance and decreasing clinical symptoms in Fabry disease.26

Surgical Care

Kidney transplantation often is beneficial. Kidney transplantation improves survival. In addition to restoring renal reserve, the transplanted kidney produces a portion of the lacking enzyme alpha-galactosidase.

Consultations

  • Nephrologist: Kidney failure is responsible for most fatalities associated with angiokeratoma corporis diffusum. A nephrologist can determine when renal dialysis and transplantation are indicated.
  • Neurologist: Patients describe the pain associated with nerve involvement of Fabry disease as excruciating. In addition, a number of CNS problems are associated with this condition.
  • Cardiologist: In addition to congestive heart failure and hypertension resulting from renal impairment, frequent primary dysfunction of the heart occurs.
  • Pulmonologist: As the lung vasculature becomes increasingly affected, obstructive pulmonary disease often develops.
  • Geneticist: Genetic counseling is helpful in this genetically transmitted disease.

Diet

A low-salt, high-protein diet may be used to help stave off renal problems, peripheral edema, and congestive heart failure.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Early intervention with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently and clearly decreases Gb3 levels in the blood plasma and clears vascular endothelial cellular lysosomal inclusions. While effects on other tissue are no so obvious, ERT, when initiated early, seems to prevent cellular damage and disease complications.27

Lidove et al28 noted that 2 formulations of the enzyme alpha-galactosidase A are used in Europe: agalsidase alpha (produced in a human cell line) and agalsidase beta (produced in Chinese hamster ovary cells). Two different enzyme preparations are made by different companies: agalsidase alpha (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme).

Lidove et al,28 based on a review of 11 trials, reported that these preparations both appear to have clinical efficacy but that further assessments are needed. The trials have not been optimal in design and would benefit from a prospective design and a specific investigation into the effects of ERT in women and on the use of ERT early in the course of Fabry disease to halt organ damage before it starts. Additionally, Kim et al29 noted that the pulmonary manifestations of Fabry disease respond positively to ERT.

Anticonvulsants

Antiseizure medications are the most helpful in alleviating the debilitating pain of neurologic involvement.


Phenytoin (Dilantin)

May act in motor cortex where may inhibit spread of seizure activity. Activity of brainstem centers responsible for tonic phase of grand mal seizures also may be inhibited.
Individualize dosing; if dose cannot be divided equally, larger dose should be taken before retiring for the evening.

Adult

100-200 mg PO bid/tid

Pediatric

4-8 mg/kg PO divided bid/tid
>6 years: May require minimum adult dose (300 mg/d); not to exceed 300 mg/d

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity; effects 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, oral contraceptives, and valproic acid; coadministration of acetazolamide and phenytoin may produce osteomalacia if these medications are used on a long-term basis; TCAs may lower seizure threshold in epileptic patients stabilized on anticonvulsants; concurrent use of phenytoin and clofazimine may result in reduced phenytoin efficacy; diltiazem is documented to result in clinically significant elevations in phenytoin serum levels associated with signs and symptoms of phenytoin toxicity; concurrent use of folic acid and phenytoin has resulted in increased seizure frequency and decreased phenytoin levels in some patients; significantly increased phenytoin levels reported with concurrent use of phenytoin and nafimidone in epileptic patients; concurrent administration of phenytoin and viloxazine may produce elevated phenytoin serum concentrations

Documented hypersensitivity to drug or related agents, sinoatrial block, second- and third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform CBC counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue if rash appears, and do not resume if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood glucose level); discontinue if hepatic dysfunction occurs; abrupt withdrawal may precipitate status epilepticus; nephrotoxicity that includes interstitial nephritis, nephrotic syndrome and renal failure reported with therapeutic phenytoin use; coarsening of facial features, enlargement of lips, and hypertrichosis has occurred with phenytoin therapy; phenytoin interferes with vitamin D metabolism and may cause osteomalacia; long-term phenytoin therapy is associated with symptomatic and asymptomatic peripheral neuropathy and neuromuscular disorders


Carbamazepine (Tegretol)

May reduce polysynaptic responses and block posttetanic potentiation.

Adult

100 mg PO bid/tid; not to exceed 1200 mg/d

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels); coadministration with erythromycin may increase serum levels; doses of carbamazepine may need to be increased in patients receiving antineoplastic therapy with doxorubicin or cisplatin

Documented hypersensitivity to drug or related products; history of bone marrow depression, MAOIs within last 14 d

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Not for use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness; adverse effects include acute intermittent porphyria, acute renal failure, agranulocytosis, aplastic anemia, AV block, bone marrow depression, cardiac dysrhythmia, congestive heart failure, drug-induced eosinophilia, hepatitis, leukocytosis, leukopenia, nephrotoxicity, systemic lupus erythematosus, thrombocytopenia, and toxic epidermal necrolysis
Caution in breastfeeding, elderly patients, history of adverse hematological reaction to any drug, history of cardiac damage, increased intraocular pressure, kidney dysfunction, liver dysfunction, and history of atypical absence seizures; MAOIs must be discontinued for a minimum of 14 d before starting carbamazepine; patients with underlying mental illness may experience activation of latent psychosis or agitation; do not discontinue abruptly; patients receiving carbamazepine therapy should avoid grapefruit juice consumption


Alpha-galactosidase A (alpha-Gal A)

Recombinant form of human enzyme alpha-galactosidase A, levels of which are deficient in persons with Fabry disease. Data from clinical trials show decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, 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 (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 over 4-6 h (initial infusion); subsequent infusions may be administered at 3-5 mg/min; repeat q2wk
Replagal: 0.2 mg/kg IV over 40 min q2wk
Maintenance dose not established

Pediatric

Not established; appropriate time to initiate treatment in children has not been determined

Amiodarone, chloroquine, monobenzone, or gentamicin may inhibit intracellular alpha-galactosidase activity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause IgG antibody production (55% with Replagal; 83% with Fabrazyme); may cause allergic reactions (10% Replagal, 59% 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; higher risk of severe complication from infusion reactions in compromised cardiac function

More on Angiokeratoma Corporis Diffusum (Fabry Syndrome)

Overview: Angiokeratoma Corporis Diffusum (Fabry Syndrome)
Differential Diagnoses & Workup: Angiokeratoma Corporis Diffusum (Fabry Syndrome)
Treatment & Medication: Angiokeratoma Corporis Diffusum (Fabry Syndrome)
Follow-up: Angiokeratoma Corporis Diffusum (Fabry Syndrome)
References
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Further Reading

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Keywords

angiokeratoma corporis diffusum, Fabry syndrome, Fabry disease, Fabry-Anderson disease, FD, Fabry's disease, Anderson-Fabry disease, angiokeratoma, AKCD, angiokeratoma corporis diffusum

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Optigenex Consulting fee Independent contractor

Coauthor(s)

Anusuya Mokashi, MS, MD, Radiology Resident, Staten Island University Hospital
Disclosure: Nothing to disclose.

Arnold R Oppenheim, MD, Assistant Professor, Department of Internal Medicine, Division of Dermatology, Eastern Virginia School of Medicine
Arnold R Oppenheim, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Clinical Pathology
Disclosure: Nothing to disclose.

Medical Editor

Timothy McCalmont, MD, Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco; Editor-in-Chief, Journal of Cutaneous Pathology
Timothy McCalmont, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society of Dermatopathology, California Medical Association, College of American Pathologists, and United States and Canadian Academy of Pathology
Disclosure: Apsara Consulting fee Independent contractor

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Rosalie Elenitsas, MD, Herman Beerman Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System
Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis  investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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