FABRY DISEASE

Fabry disease (FD) is a genetic disorder related to mutations in the GAL gene on chromosome X, locus Xq22.1 with a pattern of X-linked recessive inheritance. This fact indicates the gravity differentiated by gender, making the male patients affected with the classic form of FD more seriously, with a reduced survival, hardly beyond the sixth decade of life. (1-2).

 

Diagnosis

The diagnosis can be done by measuring the enzyme alpha-galactosidase or alpha-GAL (blood tests that measure the activity of the enzyme alpha-GAL) and mutation or genetic analysis (blood collection for DNA analysis). In men, this enzyme will almost always be low and in most cases the enzyme assay in leukocytes is enough in order to confirm the diagnosis. In women, the enzyme test can be normal, so it is necessary to perform the molecular test for the detection of mutations in the gene Gal to confirm the diagnosis.

After an evaluation of the natural history of the FD established and suspected  presence of signs and symptoms, diagnostic confirmation by additional tests may be done as follows:

In male suspected patients:

  • Analysis of the enzyme alpha-Galactosidase A in the plasma
  • Analysis of the leukocyte enzyme alpha-Galactosidase A; more sensitive than the analysis of plasma.
  • Analysis of mutation in the alpha Gal gene, in men, is rarely needed. This test is restricted to  atypical cases where the enzymatic assessment is doubtful.

In female suspected patients:

  • Analysis of mutation in the alpha Gal; in women,  the enzyme assay (analysis of Alpha-Galactosidase A) may be normal, so the molecular test is considered mandatory to confirm the diagnosis, except in cases where the woman is  heterozygous, and the father is a known carrier of FD.

Note: Skin and/or kidney biopsy can also be done in both sexes, however, depending on the other methods, nowadays biopsy is rarely used for diagnosis confirmation.

We currently have two formulas for enzyme replacement therapy (ERT) with recombinant enzyme available for the treatment of FD.

A study done by the NIH in male homozygotic patients, treated with alpha agalasidase (0.2 mg / kg) showed a significant decrease of plasma levels and urinary Gb3 and a significant reduction of the neuropathy.

A multicenter study, including males and female patients with FD, with agalasidase beta (1mg/kg) also showed a significant decrease in the concentration of Gb3 in renal, heart and skin tissues. Besides a significant improvement in patients' pain complaints.Several studies have demonstrated the effectiveness of ERT in improving symptoms, reducing the severity and progression of FD and providing a longer survival.

 

Enzyme replacement therapy (ERT) with Fabrazyme (beta agalasidase)

Before using this drug, Fabrazyme (beta agalasidase), the label should be consulted. The contents described in Datagenno may not contain all the side effects and risks described in the instructions of the manufacturer.

The agalasidase alpha is produced by a strain of genetically modified human cells.

Dosage: 0.2 mg / kg every 14 days infusion time minimum 40 minutes, when using 0.2 micron filter in serum catheter, it is not necessary to use the infusion pump.

The infusion should be discontinued if adverse effects appear, the effects should be treated and the infusion can be resumed 10 minutes after symptom improvement.

 

Enzyme replacement therapy (ERT) with Fabrazyme (beta agalasidase)
Before using this drug, Fabrazyme (beta agalasidase), the label should be consulted. The contents described in Datagenno may not contain all the side effects and risks described in the instructions of the manufacturer.

The beta agalasidase produced by a hamster cell line is also genetically modified. Both therapies were shown to be effective in treating DF in reducing the severity and / or progression of clinical manifestations of disease.

Dosage: 1mg/kg every 14 days, minimum infusion time of 120 minutes, always use the infusion pump and filter of 0.2 microns in serum gear. The initial infusion rate should not exceed 0.25 mg / min (15 mg / hour), once established the patient's tolerance for the infusion, the rate may be increased in increments of 0.05 to 0.08 mg / min in subsequent infusions (3-5 mg / hour). Maximum infusion rate: patients with less than 30 kg is from 0.25 mg / minute, over 30 kg patient, the infusion time must be at least 120 minutes.

The drug should be reconstituted and used within 3 hours after reconstitution, the total time of recovery until the end of infusion should not exceed 24 hours.

The infusion should be discontinued if adverse effects appear, the effects should be treated and the infusion can be resumed 10 minutes after symptom improvement.


Monitoring  patients on ERT

Currently, there is no consensus for  monitoring of patients on enzyme replacement therapy (ERT) for Fabry disease; however, these patients should be periodically monitored by a criteria taking into account the symptoms, criteria severity and possible side effects .

Renal impairment:

  • Complete blood count
  • Urea
  • Creatinine
  • Proteinuria in 24 hours
  • Use of the inhibitor of angiotensin-converting enzyme or angiotensin blocker receptoresda in order to reduce proteinuria and control blood pressure (BP)
  • Control of BP should be done in order to maintain levels of BP <130X80 mmHg to

Cardiac involvement:

  • Eletrocardiogram every 6 months
  • Echocardiogram every 12 months

Oftalmologic commitment:

  • Evaluation of fundus for the detection of Cornea Verticillata, an important signal in FD

Note: The level of Gb3 (globotriaosylceramide) in plasma or urine is an important marker of disease development. The biopsy for assessing the deposit of Gb3 in the kidney by electron microscopy, can also be done as a control to predict the results of ERT on renal function.

 

Adverse effects of ERT

The most common reactions are the infusion, which, when present, most often occurring within one hour after infusion and the low severity. The most common symptoms may be chills, dyspnea, flushing, fever, hypertension, nausea, chills, tachycardia, urticaria, and vomiting.

Severe reactions such as nausea, fever, chills, tachycardia, urticaria, vomiting are rare and mostly occur within 4 months of initiating therapy.

The use of corticosteroids and antihistamines and oral antipyretics should be refered for 1-3 hours before infusions in patients with a history of infusion reactions.

 

Contraindications

Hypersensitivity to Alfa galasidase or any component of the formulation.

Concomitant use with chloroquine, amiodarone, monobenzone, or gentamicin (these agents have the potential to inhibit the intracellular activity agalsidase alfa).

Precautions related to adverse effects:

  • The formation of antibodies: About 55% of patients treated IgG is presented after a period of 3 months from the start of therapy. In approximately 60% of these patients have been shown to free antibody.

In more than 80% of the cases, patients demonstrate immunological tolerance on the basis of low antibody titers within 12-18 months.