Introduction
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is an ultra-rare, progressive and fatal autosomal recessive disorder. It is a multi-organ disease characterized by cachexia, gastrointestinal dysmotility, ptosis, peripheral neuropathy, sensorineural deafness and leukoencephalopathy with intact cognition in most studied patients. MNGIE is caused by loss of thymidine phosphorylase (TP) activity due toTYMP mutations which lead to toxic increase in levels of thymidine and deoxyuridine in plasma and tissues. The accumulation of nucleosides results in unbalanced pools of intramitochondrial deoxynucleotides causing point mutations and deletions, thus impairing mitochondrial DNA (mtDNA) replication and leading to mtDNA depletion. As a consequence, patients develop progressive mitochondrial respiratory chain oxidative phosphorylation dysfunction resulting in a multisystem mitochondrial disorder. The disease is progressive and death is primarily due to severe malnutrition and gastrointestinal complications such as perforations and peritonitis. Other infections originate frequently from central venous catheters used in patients with MNGIE for chronic total parenteral nutrition (TPN) as the main, sometimes even the only source of nutritional intake. Most patients die between the 3rd and 4th decade.
Over the years, attempts to reduce toxic nucleoside accumulation by hemodialysis failed because of rapid re-accumulation of thymidine. Enzyme replacement therapy provided as erythrocyte-encapsulated TP showed some efficacy in a very few patients but needs to be repeatedly infused. A trial of repeated transfusions of platelets, which are rich in TP, produced transient reduction of nucleoside levels. This therapeutic modality could not constitute a long-term therapy but raised the concept of performing HSCT as a continuous lifelong replacement therapy of TP by the donor-derived cells which are rich in TP Since nucleosides diffuse between extra-and intracellular compartments, TP from normal donor cells has been shown to clear thymidine and deoxyuridine from plasma and presumably also from tissues of patients with MNGIE. We performed repeated platelet infusions in three patients, which resulted in ~40% transient reduction of the nucleoside levels and led us to perform the first HSCT in a patient with MNGIE in 2005. Since 2005 to 2016 we have performed allogeneic HSCT in 6 patients with MNGIE disease from 3 consanguineous families. Here we describe our single center experience with long-term follow up.