Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.
Highlights
Mitochondrial diseases represent a genetically and clinically heterogeneous group of disorders caused by mutations in mitochondrial DNA, that affect synthesis and function of mitochondrial proteins, such as tRNA and ND1, 4, 6 (DiMauro, 2004)
A subtype of the latter is mitochondrial DNA depletion syndrome (MDS); a group of mainly autosomal recessive disorders caused by defects in nuclear genes involved in mitochondrial DNA (mtDNA) replication (e.g., DNA polymerase subunit gamma (POLG) and PEO1 causing hepatocerebal MDS), or genes crucial for maintenance of mtDNA including thymidine kinase 2 (TK2), ribonucleotide reductase M2 B (RRM2B) and thymidine phosphorylase (TYMP) gene mutations associated with Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (El-Hattab and Scaglia, 2013)
A strategy that can be applied for other similar mitochondrial disorders that are caused by altered nucleosides and deoxyribonucleoside triphosphates (dNTP) metabolism, for example in disorders caused by mutations in TK2 or deoxyguanosine kinase (DGUOK) deficiency (Camara et al, 2014)
Summary
Mitochondrial diseases represent a genetically and clinically heterogeneous group of disorders caused by mutations in mitochondrial DNA (mtDNA), that affect synthesis and function of mitochondrial proteins, such as tRNA (in MELAS disease) and ND1, 4, 6 (responsible for the majority of cases in LHON disease) (DiMauro, 2004). Another group is caused by mutations in nuclear DNA (nDNA) that lead to defects in nuclear encoded mitochondrial proteins. Due to its variable clinical presentations, MNGIE can be overlooked or misdiagnosed as Crohn’s disease, psychiatric disorder, anorexia nervosa, or myasthenia gravis (Rickards et al, 1994; Teitelbaum et al, 2002; Marti et al, 2004)
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