THE PERPETUATION OF HEMOPHILIA BY MUTATION

Abstract

Sporadic cases of hemophilia, constituting approximately one third of all patients with hemophilia A and one fifth of patients with hemophilia B, have been ascribed to mutations or ignorance of the family history. Previous descriptions have not noted a preponderance of severe cases in the sporadic group. In our families sporadic occurrence was strikingly associated with severe disease. In 94 families with hemophilia A a single case per kinship occurred in 36 of 60 families with severe disease, and in only 2 of 34 families with non-severe disease. Similarly, 4 sporadic cases, all of them severe, occurred among 17 families with hemophilia B.

The distribution of Factor VIII levels in mothers and maternal grandmothers of sporadic cases of severe hemophilia A was compared to that in groups of confirmed female carriers and normal women. From this comparison it was concluded that in the majority of these families the hemophilic gene arose by recent mutation. On the basis of the frequency of hemophilia in the newborn population and the frequency of de novo cases the mutation rates for hemophilia A and B were estimated as slightly less than 4.2X10^-5 and 0.46X10^-5, respectively. Results were comparable to figures obtained on the basis of the reduced reproductive fitness of affected males. Due to a lower reproductive fitness in severe disease, a greater mutation rate is expected to balance the loss of genes for hemophilia. This is reflected in the preponderance of severe over non-severe disease among the de novo cases.

The results of this study underscore the importance of both personal and family history in the detection of the disease.