X-linked Recessive Inheritance
Posted by Surgery on Sep 3, 2008
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In the previously discussed autosomal modes of inheritance, males and females are equally likely to be affected and transmission does not depend on the sex of the parent. This is in contrast to X-linked or sex-linked conditions. Genes for X-linked recessive (XLR) conditions are located on the X chromosome. When a gene is abnormal on one X chromosome in females, the normal gene on the other X chromosome can compensate for the abnormal one. However, a male who inherits an abnormal X is hemizygous, because there is no corresponding gene locus on the Y chromosome, and therefore has the condition. The probability that male offspring of female carriers will be affected is 50%, whereas female offspring have a 50% chance of being a carrier, but are not affected. X-linked inheritance is distinguished from AD inheritance by the absence of male-to-male transmission.
Although most females carrying a mutation for an XLR disorder are asymptomatic, this is not always the case. During embryogenesis in females, one of the X chromosomes undergoes a process known as X-inactivation, or lyonization. This process is random; the maternally and paternally derived X chromosomes have an equal chance of becoming inactivated. However, the same X remains inactivated in daughter cells of the original cell. If by chance, in a large proportion of cells in the involved organ, the normal X chromosome has been turned off, the woman can show symptoms of the XLR disorder. Hemophilia A (classic hemophilia) (MIM 306700), the most common of the severe congenital coagulation disorders, is inherited in an XLR fashion. Patients with this condition have a reduced coagulant activity of factor VIII in the coagulation cascade, either due to the decreased production of the protein or formation of an abnormal protein that does not work properly. Reduced factor VIII activity leads to recurrent hemarthroses, deep muscle hematomas, intracranial bleeds, and hematuria. Patients are also at an increased risk of bleeding following trauma and surgery. Hemophilias A and B occur in approximately 1 in 5,000 male births, with nearly 80% having hemophilia A (21). In general, the activity of factor VIII in affected males is either absent or severely decreased. Factor VIII activity in female carriers is also reduced, on average, to 50% of normal. However, in about 10% of female carriers, the level of factor VIII activity can be significantly reduced because of inactivation of a high proportion of the normal X chromosomes in the cells of the liver. This can sometimes result in a mild bleeding disorder (22). Several mutations have been identified in the factor VIII gene. An intron 22 inversion has been observed in 45% of patients with severe hemophilia A (22), whereas an intron 1 inversion accounts for 3% of cases (23). Factor VIII gene deletions or rearrangements, frameshift, splice junction, and nonsense mutations account for about 40% of mutations in severe hemophilia A, with about 10% of mutations being missense. In contrast, the vast majority of mutations in mild to moderately severe hemophilia A (97%) are missense mutations (22). In some cases, the mutation cannot be identified and DNA diagnosis must rely on linkage analysis (discussion follows).
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