Hemophilia genetic factors

The penetrance of genetic factors is another parameter in complex diseases. If the penetrance of these factors is indeed very low, as studies to date indicate, new approaches wiU be necessary to detect them. It seems already dear that the relative genetic risk of single variants is very small in complex diseases. Therefore, predictions can only provide risk probabilities but not risk certainties. On the other hand, in cases of low complexity and single nucleotide polymorphisms (SNPs) with high penetrance, the predictive power of tests reaches close to certainty as shown for hemophilia. 

Hemophilia A Is Due to a Genetically Determined Deficiency of Factor Vlll... 

Genetic disorders of coagulation factors occur, and the two most common involve factors VIII (hemophilia A) and IX (hemophilia B). 

BeneFIX Human factor IX Genetics Institute Treatment of hemophilia B... 

Recombinate Antihemophilic factor Baxter Genetics Institute Hemophilia A... 

Refacto Antihemophilic factor Genetics Institute Hemorrhagic episodes and surgical prophylaxis in patients with hemophilia A... 

Direct tests have been applied to sickle-cell disease, thalassemia, and hemophilia A and have documented this great genetic diversity. About 100 defective gene sites have been identified for thalassemia, and there may be more than 1000 associated with the factor VIII gene. 

Clinical trials have demonstrated excellent efficacy with recombinant human factor VIII concentrates available as Recombinate and Kogenate. These recombinant factor VIII products are purified from the cell culture of plasmids, not viral DNA-transfected hamster cells and therefore do not express viral sequences. The addition of human serum albumin for stabilization, constitutes the sole possible source for human viral contamination. More recently recombinant factor IX has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been proved to be safe and effective in the treatment of patients with hemophilia B. 

Replacement of deficient gene products or even of organs is also utilized in the treatment of genetic disorders for example, replacement of coagulation factor VIII in hemophilia A, of or-antitrypsin in persons deficient in this factor or of pancreatic islet cells in some forms of diabetes mellitus. 

Becker J, Schwaab R, Moller-Taube A, Schwaab U, Schmidt W, Brackmann HH, Grimm T, Olek K, Oldenburg J. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet 1996 58(4) 657-670. 

Kay MA, Manno CS, Ragni MV et al. (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients with an AAV vector. Nature Genetics 24 257-261 Kung J, Hagstrom J, Cass D et al. (1998) Human FIX corrects bleeding diathesis of mice with hemophilia B. Blood 91 784-790... 

Factor 8 KoGENate FS (Bayer) Recombinate AHF (Baxter) Bioclate (Baxter) ReFacto (Wyeth/Genetics Institute) Helixate FS (Aventis Behring) Advate (Baxter) Hemophilia A... 

Factor 9 BeneFIX (Wyeth/Genetics Institute) Hemophilia B... 

Risk factors for developing an inhibitor are the severity of the hemophilia, age (under 30 years), genetic predisposition, antigenicity of factor replacement therapy, and race (increased prevalence among black people) (9). In addition, it has been suggested that changing from one product to another can also stimulate the development of inhibitors (10). 

Anaphylaxis in conjunction with inhibitor development has been described. Patients with hemophilia B with complete gene deletions have the greatest risk of anaphylaxis, with a minimum risk of 26%, whereas the risk in patients with null mutations was 2.4% and nearly zero for mis-sense mutations (13). Predisposing factors for the development of anaphylaxis, besides mutation type, are genetic predisposition and environmental experience, such as the type and frequency of factor IX product (13). 

Antonarakis S. Molecular genetics of coagulation factor VTII gene and hemophilia A. Thromb Haemost 1995 74 322-8. 

Jenkins PV, CoUins PW, Goldman E, McCraw A, Riddell A, Lee CA, et al. Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A implications for genetic counseling. Blood 1994 84 2197-201. 

Lakich D, Kazazian HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe hemophilia A. Nature Genet 1993 5 236-41. 

Transgenic animals can also secrete proteins such as blood clotting factors needed by human hemophilia sufferers in their milk (Suraokar and Bradley, 2000). On these lines, Polly, a genetically altered sheep was created at the Roslin Institute in Scotland to produce milk that contained the protein used to treat human hemophilia (Pettus, 2006). 

Classical studies of the recessive, sex-linked disorder hemophilia provided evidence that a gene concerned with the synthesis of factor VIII must be situated on the X-chromosome. When it was discovered that a reduction in factor VIII was commonly present also in von WUlebrand s disease, with a somatic dominant inheritance, it became clear that another gene, on an autosome, must also be involved. Cross-transfusion experiments between patients suffering from hemophilia and von Willebrand s disease show-ed that hemophilic blood would stimulate factor VIII synthesis in von Willebrand s disease, but not vice versa. These data have made it possible to construct a number of alternative genetic models now being submitted to critical experimentation. 

On the lines just discussed, it is possible to construct a simple model of the genetics of factor VIII synthesis in von Willebrand s disease and hemophilia. This model will be discarded because it will not explain all the facts, but it may be easier to accept the greater complexities of models proposed by J. B. Graham and outlined below when the defects of a simpler model have been grasped. 

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