Hemophilia A

From Iusmgenetics

Contents 1 Hemophilia A 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Hemophilia A

General background information

Mode of inheritance

• X-linked recessive

Single important gene

• The FVIII gene makes the clotting cascade enzyme Factor VIII.
• The gene is large: 186 kb with 26 exons.

Etiology

• There are a variety of mutations and mutation types (large / small deletions, insertions, missense, etc.) that cause hemophilia A.
  • We will use Hemophilia A specifically as an example of unusual crossing over.
    • Occurs in 40-50% of Hemophilia A cases

• Unusual crossing over:
  • In hemophilia A, an inversion within the gene arising from crossing over causes disruption of the gene.
  • The inversion in Hemophilia A usually occurs during male meiosis.
  • Recall that exons are numbered for their position (starting with 1) as one moves in the direction of transcription.
  • The wild-type order is 1->26.
  • There are, however, inverted repeats downstream of the first exon and upstream of the 22nd exon that can pair to allow inversion.
  • The inversion flips exons 1-22 over, leaving the final order 22->...->1->23->...->26

Pathogenesis

• Pts with > 25% function of factor VIII of the clotting cascade will have no symptoms.
  • As the amount of factor VIII function approaches 5% of normal, symptoms begin to manifest.
  • < 1% factor VIII function manifests severe disease: frequent bleeding (even spontaneously), bleeding into joints

Phenotypic information

• External bleeding episodes
• Prolonged bleeding from a circumcision wound or a venepuncture or heelprick is another common early sign of haemophilia
• Prolonged bleeding from common injuries, or in severe cases bleeds may be spontaneous and without obvious cause.
• The most serious sites of bleeding are: joints, muscles, digestive tract, and brain
  • The muscle and joint haemorrhages are indicative of haemophilia
  • Digestive tract and cerebral haemorrhages are also germane to other coagulation disorders
• Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability.
  • Joint damage is not a result of blood in the capsule but rather the healing process.
  • When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded.

Diagnosis

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers