Pediatric Clinics of North America - CIPERJ

ADVANCES IN HEMOPHILIA
371
Carrier state and genetic testing in hemophilia
Carrier status in women cannot be established based solely on factor VIII
or IX levels because there is a significant overlap between factor levels in
carrier and noncarrier women. For this reason, genetic testing is recommended.
Women who are obligate carriers (daughter of a man who has hemophilia
or the mother of more than one son who has hemophilia) do not
need carrier testing as it is evident that they have inherited an affected X
chromosome from a father who has hemophilia (see Fig. 1).
In approximately 30% of patients who have hemophilia, there is no family
history of the disease and it seems to occur as a result of spontaneous
novel mutations [44]. In such cases, molecular testing can identify mutations
in 95% to 98% of patients who have hemophilia A or B [45].
Candidates for genetic testing include patients who have a diagnosis of
hemophilia A or B, at-risk women who are related to an affected man (proband)
who has a known mutation, and female carriers of hemophilia A or B
seeking prenatal diagnosis.
Although in many cases the whole gene needs to be sequenced, this is not
necessarily the case for patients who have severe hemophilia A, in whom intron
22 inversion is found in approximately 45%. In hemophilia A, therefore,
it is recommended initially to perform intron 22 gene inversion
analysis and, if not present, to proceed with full sequencing of the factor
VIII gene. For patients who have mild or moderate hemophilia A, full sequencing
of the factor VIII gene is recommended unless a mutation already
is identified in another family member. To identify a mutation in patients
who have hemophilia B, full sequencing of the factor IX gene is performed.
After a mutation is identified in a proband with hemophilia A or B, carrier
testing and prenatal diagnosis can be offered to at-risk family members. If
a proband is not available for testing, genetic analysis can be performed
on a blood sample from an obligate carrier.
Potential new therapies in the horizon
Gene therapy
Gene therapy involves the transfer of genes that express a particular gene
product into human cells resulting in a therapeutic advantage. Particularly
for hemophilia, the goal of gene transfer is aimed at the secretion of a functional
factor VIII or IX protein. Different strategies for hemophilia using
animal models or humans include retroviral, lentiviral, adenoviral, and adeno-associated
viral vectors.
There have been several gene therapy phase I clinical trials using direct in
vivo gene delivery or ex vivo plasmid transfections with hepatic reimplantation
of gene-engineered cells [46,47]. Even though a therapeutic effect has
been seen in some of these studies, stable production of the coagulation