Haemophilia B: From Molecular Diagnosis to Gene Therapy

Abstract

Thanks to its typical expression, haemophilia can be identified in writings from the second century AD. Haemophilia B, an X-linked recessive bleeding disorder due to factor IX (FIX) deficiency, has an incidence of about 1:30,000 live male births. The factor 9 (F9) gene was mapped in 1984 on Xq27.1. Haemophilia is diagnosed from prothrombin time, activated partial thromboplastin time, and FIX levels. Carrier females are usually asymptomatic and must be identified only with molecular analysis. Linkage analysis of F9 polymorphisms is rapid and inexpensive but limited by non-informative families, recombinant events, and the high incidence of germline mutations; thus, various procedures have been used for the direct scan of F9 mutations. We set up a novel denaturing high performance liquid chromatographic procedure to scan the F9 gene. This rapid, reproducible procedure detected F9 mutations in 100% of a preliminary cohort of 18 haemophilia B patients. Parallel to the development of more efficient diagnostic tools, the life expectancy and reproductive fitness of haemophilic patients have greatly improved and will continue to improve thanks to the use of less immunogenic recombinant FIX. Hopefully, new approaches based on gene therapy now being evaluated in clinical trials will revolutionise haemophilia B treatment.

Prenatal diagnosis of inherited diseases: 20 years’ experience of an Italian Regional Reference Centre

“…Indeed, most physicians help our centre to promote screenings in the early phases of pregnancy for diseases like haemoglobinopathies [14] or cascade screenings for diseases like CF and haemophilia [33,34], and to collect the mutational data of all known patients in a database [34]. This is particularly useful for X-linked diseases where a de novo mutation occurs in more than 30% of cases [28,35].…”

The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B

“…Hemorrhage into internal organs and the central nervous system may also occur. [1][2][3] The goal of hemophilia treatment is to treat or prevent hemorrhage, reduce disabling joint and tissue damage, and improve quality of life and life expectancy. Historically, the mainstay of hemophilia B therapy has been the replacement of deficient FIX with pooled plasma or plasma derivatives.…”

Prenatal diagnosis of haemophilia: our experience of 44 cases

“…Depending on FVIII/FIX coagulant activity, haemophilia is classified as severe (FVIII:C/FIX, < 1%), moderate (FVIII:C/FIX, 1%-5%) and mild (FVIII:C/ FIX, > 5%). Severe haemophilia accounts for about twothirds of cases [1,2].…”

“…For HB, gene scanning procedures like denaturing high performance liquid chromatography (DHPLC) or gene sequencing are used [5]. In about 5% of HA/HB cases negative to mutation analysis, carrier and prenatal diagnosis (PD) can be made by linkage analysis testing microsatellites associated with F8C or F9 genes [1,2].…”