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The incidence of inhibitor development according to specific mutations - and treatment?

The spectrum of mutations in the factor VIII (FVIII) gene was investigated in a cohort of patients with severe haemophilia A, together with the relationship between mutation type and inhibitor development. DNA analysis was undertaken on 55 previously untreated patients in the Recombinate PUP mutation study who had all received the same clotting factor treatment and underwent regular monitoring for inhibitor development. Overall, 35% of patients with 'severe molecular defects' - intron 22 inversions, large deletions or stop mutations - developed an inhibitor. None of the patients with small insertions or deletions developed inhibitors. The patient numbers in this study were too small for analysis of mutation location effect and therefore an analysis of a large electronic patient database, HAMSTeRS, was undertaken. This revealed that 40% of patients with large deletions and 35% of patients with nonsense mutations developed inhibitors. This large database of information allowed further stratification by examination of the location of mutations within the FVIII gene and the type of sequence affected by the mutation. Nonsense and missense mutations in the light chain were associated with a higher risk of inhibitor formation than those occurring in the heavy chain. Small deletions or insertions affecting an A residue in a run of A residues were associated with a lower risk of inhibitor formation than deletions or insertions affecting other sequences. Splicing errors demonstrated the lowest inhibitor risk of any mutation type. These results may enable patients at higher risk of inhibitor formation to be identified. This may have consequences for the design of clinical trials and treatment options available to high-risk patients.