Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

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.

Mitochondrial Neurogastrointestinal Encephalomyopathy Imitating Crohn’s Disease: A Rare Cause of Malnutrition

“…is a rare autosomal recessive disease caused by a mutation in the TYMP gene encoding thymidine phosphor ylase. Although the prevalence of MNGIE has not been determined, approximately 200 cases have been described worldwide [1]. Clinical manifestations, including gastrointestinal (GI) and neurological symptoms, first appear in the second decade of life [2] and may lead to a misdiagnosis of anorexia nervosa, inflammatory bowel disease, celiac disease, or Charcot-Marie-Tooth disease.…”

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

“…Ophthalmological assessments, including visual evoked potential and neuro-ophthalmologic evaluations, have revealed prolonged P100 latency and retinitis, respectively [29,49] . Audiology investigations have confirmed unilateral or bilateral sensorineural hearing impairment in some patients [29,43,59,60] .…”

“…Ocular symptoms may be treated with corrective lenses and surgery for strabismus or ptosis. Cochlear implants or auditory aids may assist patients with sensorineural hearing loss [60,81] . For patients with psychiatric symptoms, antidepressants and antipsychotics may provide benefit.…”

Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice

“…Alongside classic neurological signs (external ophtalmoplegia, leukoencephalopathy and sensorimotor peripheral neuropathy), chronic intestinal pseudo-obstruction (CIPO) is reported in almost all MNGIE patients and occurs at onset in 45–67% of cases [ 2 , 3 ]. Other gastrointestinal symptoms include early satiety, nausea, dysphagia, post-prandial emesis, abdominal pain and/or distention and diarrhea [ 4 ].…”

“…Allogeneic hematopoietic stem cell transplantation (HSCT) corrects the biochemical metabolic imbalance as donor-derived leucocytes and platelets are rich in thymidine phosphorylase [ 4 ]. It is effective to relieve CIPO in few reported MNGIE cases [ 5 ] although malnutrition often persists and most cases rely on nutritional support [ 6 ].…”