Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Abstract

Mitochondrial neurogastrointestinal encephalopathy (MNGIE), usually an autosomal-recessive inherited condition, causes gastrointestinal dysmotility, ophthalmoplegia, ptosis, leukoencephalopathy and neuropathy. The chromosome 22 disorder, due to mutations in the nuclear gene TYMP encoding thymidine phosphorylase (TP), leads to the accumulation of thymidine and deoxyuridine, with mitochondrial dysfunction. This report describes a patient with an MNGIE-like syndrome with a heterozygous TYMP mutation who showed marked, but transient improvement postallogeneic haematopoietic stem cell transplantation (HSCT). The patient, showing ptosis and ophthalmoplegia, was initially managed for myasthenia gravis. She developed gastrointestinal symptoms, dysarthria, dysphagia and weakness, and MNGIE was considered due to its low TP levels and improvement after platelet transfusions. She underwent HSCT, with dramatic improvement, but regressed 18 months later despite normal TP levels, platelet counts and full chimerism. MNGIE may encompass a spectrum of disorders. TP deficiency alone is unlikely to explain all clinical signs, and other factors, including the possible development of anti-TP antibodies, which may play a role in the pathophysiology.

Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy

“…21,24 Only allo-HSCT has been demonstrated to be metabolically and clinically effective and associated with objective evidence of health improvement in the long-term. 13,14 However, this procedure has produced high morbidity and mortality rates in MNGIE patients. 13 In recent years, gene therapy has emerged as a promising alternative for MNGIE patients.…”

“…13,14 However, this procedure has produced high morbidity and mortality rates in MNGIE patients. 13 In recent years, gene therapy has emerged as a promising alternative for MNGIE patients. Our previous work has demonstrated that ex vivo hematopoietic stem cell gene therapy (HSCGT) using a lentiviral vector was able to provide ectopic TP activity in blood cells for at least six months after transplantation of sublethally irradiated Tymp/ Upp1 dKO mice.…”

“…Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been demonstrated to be an effective treatment in several patients. [12][13][14] Nonetheless, allo-HSCT is limited by the difficulty of finding suitable donors and the high mortality and morbidity rates associated with this procedure, especially in MNGIE patients, who are usually in poor clinical condition when treated. Thus, allo-HSCT may be relevant only for a subset of MNGIE patients who have HLA-matched donors and are not severely medically compromised by the disease.…”

“…The limitation of this murine model of the disease (the only one so far available) constitutes a significant issue for preclinical in vivo studies; the absence of clinical phenotype makes it difficult to evaluate whether correction of the biochemical imbalances is an appropriate demonstration of efficacy of the treatment. However, there are repeated observations that the normalization (or at least, significant reductions) of systemic dThd and dUrd levels achieved by bone marrow transplantation, 13 peritoneal dialysis, 23 or infusion of erythrocyte-entrapped TP 24 is associated with transient or long termmaintained clinical improvement in MNGIE patients. Therefore, the demonstration that a therapy is able to restore the biochemical homeostasis in the murine model should be combined with the increasing evidence, obtained from other treatments tested in MNGIE patients, that such biochemical restoration is beneficial.…”

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy

“…The question of whether leukoencephalopathy is a reversible feature cannot be solved at present. Long-term follow-up of patients with bone marrow 34,35 and liver transplantation 36 will likely provide an answer.…”