Abstract

MNGIE is a fatal, autosomal recessive disorder caused by mutations in TYMP, a nuclear gene encoding thymidine phosphorylase (TP), leading to accumulation of thymidine (dThd) and deoxyuridine (dUrd) in all tissues. This impairs mitochondrial DNA (mtDNA) replication and repair, causing mtDNA depletion and ultimately mitochondrial failure and the clinical features which include enteric neuromyopathy, peripheral polyneuropathy and progressive external ophthalmoplegia. We attempted treatment in three patients with TP encapsulated in autologous erythrocytes. Patient 1: at 3 days post infusion, the urinary excretion of dThd and dUrd decreased to 6% and 13%, respectively. This was not sustained but the results were encouraging, particularly as a low dose was administered. Patient 2: 31 treatment cycles were administered over 24 months. Pre-therapy plasma dThd and dUrd concentrations were reduced from 9.8 μmol/l and 20.0 μmol/l respectively to mid-cycle concentrations of 2.4–5.2 μmol/l and 6.2–10.6 μmol/lrespectively. Patient 3: six cycles have been administered. In cycle 5, the plasma concentrations of dThd and dUrd were zero. Clinical improvements were noted in patients 2 and 3. EE-TP is a promising prospective treatment for MNGIE.