Hemophilia a inheritance
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Inheritance of Hemophilia A: Genetic Mechanisms and Clinical Implications
X-Linked Recessive Inheritance Pattern
Hemophilia A is a genetic disorder caused by mutations in the gene coding for coagulation factor VIII (FVIII), which is located on the X chromosome. This X-linked recessive inheritance pattern means that males, who have only one X chromosome, are predominantly affected by the disease, while females, who have two X chromosomes, are typically carriers 134. Males inherit the X chromosome from their mothers and the Y chromosome from their fathers, so a male with hemophilia A must have inherited the defective gene from his mother .
Clinical Manifestations and Severity
The severity of hemophilia A varies widely and is directly related to the level of FVIII activity in the blood. Severe hemophilia A is characterized by less than 1% of normal FVIII activity, moderate hemophilia by 2-5%, and mild hemophilia by 6-50% . This variability in clinical severity is due to different mutations in the FVIII gene, which can affect either the amount of FVIII produced or its functional activity .
Female Carriers and Rare Female Hemophilia
While females are typically carriers of the hemophilia A gene and do not exhibit severe symptoms, they can have reduced FVIII levels and may experience mild bleeding symptoms. In rare cases, females can be severely affected due to mechanisms such as skewed X-chromosome inactivation, Turner syndrome (monosomy X), or compound heterozygosity, where both parents contribute a defective gene . For instance, in a reported case of triplets, one female infant exhibited severe hemophilia A due to extremely skewed X-chromosome inactivation, while her sister was an asymptomatic carrier .
Genetic Mutations and Detection
Hemophilia A results from a variety of mutations in the FVIII gene, including deletions, insertions, and point mutations. These mutations can be detected using techniques such as Southern blotting and polymerase chain reaction (PCR) . Advances in genetic analysis, including direct DNA sequencing and other molecular techniques, have significantly improved the ability to identify specific mutations responsible for hemophilia A .
Sporadic Cases and New Mutations
Hemophilia A also exhibits a high incidence of sporadic cases, where the disease appears in families with no prior history. These cases are thought to result from new mutations in the FVIII gene . The large size of the FVIII gene and the presence of mutational hotspots, such as CG dinucleotides, contribute to the frequency of new mutations .
Conclusion
Understanding the genetic basis and inheritance pattern of hemophilia A is crucial for accurate diagnosis, genetic counseling, and management of the disease. The X-linked recessive nature of hemophilia A explains its prevalence in males and the carrier status of females. Advances in genetic testing have enhanced the detection of specific mutations, providing better insights into the disease's variability and aiding in the development of targeted therapies.
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