Fig. 3 Pedigree illustrating the X-linked recessive transmission of Fabry disease. (D Affected male; (0) carrier female.

Identification of mutations in the GLA gene can be easily performed by amplification of all seven exons using polymerase chain reaction (PCR) and direct sequencing of the DNA fragments.[14] Gene rearrangements are rare (<5%) in the GLA gene, and no whole gene deletion has been detected. To date, over 300 mutations have been identified. Details are given in the Human Gene Mutation Database (see the following web site: http://archive. The most frequent lesions are nucleotide substitutions, including missense and nonsense mutations. Small or partial deletions, small insertions, splice mutations, as well as complex mutations (insertion-deletion, inversions) have also been reported. Mutations have been found in all seven exons (Fig. 2). Most of the mutations are private (present in single families). Therefore genotype-phenotype correlations that require clinical information from unrelated patients with the same genotype are limited. Most genotypes are associated with classical forms of the disease. Some missense mutations, initially identified in cardiac variants, have also been found to be associated with classical phenotypes. A model of the human a-Gal A enzyme has recently been obtained, based on the X-ray structure of the highly homologous a-N-acetylgalactosaminidase sequence.1-15-1 It will probably further our understanding of the structural basis of Fabry-causing mutations.

Genetic Counseling and Prenatal Diagnosis

Because Fabry disease is transmitted as an X-linked trait, all sons of affected males are unaffected, but all daughters are obligate carriers (Fig. 3). For all heterozygous females, there is a 50% risk of passing the deleterious allele to a son who will be affected, and a 50% risk of passing the mutant gene to a daughter who will be a carrier. Therefore determination of the status of females, either clinically affected or related to affected males, is critical to be able to offer them a reliable genetic counseling. This can be performed more accurately by the characterization of the responsible mutation. In females identified as carriers, prenatal diagnosis can be performed using a-Gal A assay and/or molecular analysis on cho-rionic villi or cultured amniotic cells, after assessment of the fetal gender.

TREATMENT Symptomatic Treatment

Fabry disease has been managed with palliative measures, most of which are standard interventions for a specific symptom: analgesics for painful crises, valve replacement for valvular disease, anticoagulants for prevention of stroke, and so on. In patients with chronic renal disease, dialysis and renal transplantation are life-prolonging because renal failure is the most frequent cause of death in Fabry disease.

Enzyme Replacement Therapy

Recently, an enzyme replacement therapy has been developed for Fabry disease. Two different recombinant molecules have been obtained: agalsidase p or Fabra-zyme® produced in Chinese hamster ovary cells (Genzyme Corporation), and agalsidase a or Replagal® produced in human fibroblasts (Transkaryotic Therapies, Inc.). After preclinical studies in animals, both molecules have been tested in humans in two independent randomized trials.[16,17] Even if studies differed in the enzyme preparation, dose per infusion, and entry criteria, both of them suggested that enzyme replacement therapy was safe and likely to be effective, as demonstrated by the decrease in Gb3 concentrations and the renal histology improvement.1-18-1 The two enzymes have been approved in Europe and other countries and are now available for patients.

Chemical Chaperons

Enzyme enhancement by chemical chaperons has also been proposed in some cases of Fabry disease. This strategy is based on the stabilization of catalytically active but unstable enzymes, either by reversible competitive inhibitors or by substrate analogues. In a cardiac variant of Fabry disease exhibiting a missense mutation associated with a residual a-Gal A activity, intravenous infusions of galactose for 2 years resulted in a significant improvement of cardiac function.[19] This supports the use of chaperon-mediated therapy in Fabry disease and other late-onset enzymopathies with selected mutations.

Substrate Depletion

An alternative treatment for Fabry disease is substrate deprivation, based on the inhibition of the synthesis of the accumulating glycosphingolipid. This approach has been tested in a-Gal A knockout mice using D-threo-1-ethyl-endioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4), a potent inhibitor of glucosylceramide synthase—an enzyme involved in the synthesis of gluco-sylceramide, which is the precursor of neutral glyco-sphingolipids.[20] Treatment with D-t-EtDO-P4 resulted in a reduction in renal Gb3. These data suggest that Fabry disease may be amenable to substrate deprivation therapy, in particular if more specific and less toxic components are developed.

Gene Therapy

Gene therapy has been explored in the murine model of Fabry disease by using different viral vectors such as retrovirus, adenovirus, and adeno-associated virus, demonstrating the feasibility of this approach.[21-23] However, deleterious consequences recently described with retroviral and adeno-associated viruses have delayed gene therapy applications in humans for Fabry disease and other genetic disorders.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook

Post a comment