A successful strategy for preimplantation diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Preimplantation genetic diagnosis (PGD) involves the screening of biopsied cells from in vitro fertilization (IVF) generated embryos. This procedure allows the selective transfer of unaffected embryos and thus may be preferable to prenatal diagnosis for couples at high risk of transmitting genetic defects to their offspring. In this way, termination of pregnancy is avoided. We describe here the development and first clinical application of PGD for medium-chain acyl-CoA dehydrogenase deficiency (MCAD). MCAD is a common inherited metabolic disorder affecting fatty acid beta oxidation. The condition is autosomal recessive with an incidence of 1/6000-1/15 000 live births in the UK. It presents usually within the first two years of life with fasting-associated hypoketotic hypoglycaemia which may lead to coma and death. The strategy developed was based on multiplex fluorescent PCR, and adapted for single cell detection. Mutation analysis was carried out using single-strand conformation polymorphism (SSCP) with fluorescent detection. The embryos generated through IVF arrested on day two post-insemination and consequently none were available for transfer; all available blastomeres were used to confirm the accuracy and reliability of the diagnostic assays.