Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2'-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a résumé of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.

Mitochondrial Neurogastrointestinal Encephalopathy Disease: A Rare Disease Diagnosed in Siblings with Double Vision

“…However, a number of patients, including our cases, reported diplopia at the time of presentation [ 9 ]. Strabismus surgery has been shown to improve ophthalmoplegias that are due to mitochondrial disorders, but no systematic studies have investigated its effectiveness in MNGIE patients [ 14 , 15 ]. A case report of a patient with MNGIE without diplopia showed improvement in external ophthalmoplegia after strabismus surgery [ 13 ].…”

Erythrocytes as Carriers of Therapeutic Enzymes

“…In the absence of thymidine phosphorylase activity there is a systemic accumulation of thymidine and 2'-deoxyuridine which generate imbalances within the mitochondrial deoxyribonucleotide pools, causing mitochondrial DNA (mtDNA) point mutations, depletion and deletion abnormalities-and ultimately mitochondrial dysfunction. The disorder is characterized by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy [71]. Although there are no licensed therapies for patients with MNGIE, there are a number of experiment treatment approaches under investigation and this is attributed to MNGIE being one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation.…”

“…Although there are no licensed therapies for patients with MNGIE, there are a number of experiment treatment approaches under investigation and this is attributed to MNGIE being one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. Erythrocyte encapsulated thymidine phosphorylase (EE-TP) is one of these experimental approaches, where recombinant E. coli enzyme was employed as the source of enzyme [71][72][73][74]. In the first proof of concept study, one dose of EE-TP (1020 units encapsulated within 20.25 × 10 10 erythrocytes) was administered to a patient with MNGI.E.…”

Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)

“…The pathogenesis of MNGIE is a systemic metabolic derangement of nucleosides. There are several suggested approaches to correct the abnormal biochemistry, 16 but each has associated problems.…”