Treating MNGIE

Neurons, myocytes, and other highly oxidative cells are critically dependent upon the production of adenosine triphosphate by the mitochondrial respiratory chain. Although mitochondria contain multiple copies of their own genome (mtDNA), which codes for 13 essential respiratory chain proteins and 24 ribonucleic acids required for intra-mitochondrial protein synthesis, they are not self-sufficient. The majority of polypeptides (>70) involved in oxidative phosphorylation (OXPHOS) are synthesized from nuclear genes, and a growing list of nuclear-encoded proteins are also required for the maintenance of mtDNA, the coordinated expression of mtDNA genes, and the assembly of an intact respiratory chain. In recent years it has become clear that disorders of intergenomic communication, between the nucleus and mitochondrion, are a major cause of human disease (table).

The first disorder of intergenomic communication to be defined at the molecular level was mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). MNGIE is an autosomal recessive disease caused by loss-of-function mutations in the nuclear gene coding for the cytosolic enzyme thymidine phosphorylase (TP, also called endothelial cell growth factor 1, ECGF1).¹ MNGIE typically presents in late childhood with ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, and peripheral neuropathy.² Most patients with MNGIE have high levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) in urine and serum, and the diagnosis is confirmed by …