Ornithine carbamoyltransferase deficiency
- Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester M27 4HA, UK
- Dr Wraith
- Accepted 31 August 2000
The death of Jesse Gelsinger on 17 September 1999 had major effects on the gene therapy community. It brought to a halt a gene therapy clinical trial at the Institute of Human Gene Therapy, University of Pennsylvania, USA and brought to a wider audience the potential clinical problems associated with this technology.1 In addition a number of clinicians became aware of Jesse's genetic disorder, ornithine carbamoyltransferase deficiency (OCTD, McKusick 311250), for the first time. OCTD is the most common disorder of ureagenesis (prevalence 1/40 000) and is inherited as an X linked trait. The OCT gene is located on the short arm of the X chromosome (Xp21.1) and over 150 mutations have been found in OCTD families. There are no common mutations and defects include gross deletions, missense and splicing mutations, as well as small insertions and deletions.2 3 The importance of detecting mutations within families lies primarily with accurate carrier detection and prenatal diagnosis, as biochemical and enzymatic methods of detection are less reliable. In addition, as enzyme activity is not expressed in either amniocytes or chorion villus biopsy material, prenatal testing had to rely on invasive fetal liver biopsy until DNA methods became available. In certain families knowledge of the mutation may help with disease prediction.4
Although our understanding of OCTD has increased greatly over recent years our abilities to treat the severe variants of this disorder remain limited.
The urea cycle and OCT
Figure 1 shows a simplified version of the urea cycle.
Ammonia is an extremely toxic molecule and organisms have evolved a number of different ways of excreting this waste product of protein metabolism. Where water is abundant (for example, fish) ammonia is directly excreted …