Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE)

Abstract

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive condition. Deficiency of thymidine phosphorylase disrupts the nucleoside pool, with progressive secondary mitochondrial DNA damage. MNGIE is clinically diagnosable because of a distinctive tetrad of gastrointestinal dysmotility, progressive external ophthalmoplegia, demyelinating neuropathy and asymptomatic leucoencephalopathy. The diagnosis may be confirmed genetically or biochemically. Misdiagnosis is frequent, but early and accurate recognition allows the possibility of novel transplant therapies capable of rectifying the biochemical defects. Its management remains difficult in the face of progressive disability and the risks of treatment.

A novel thymidine phosphorylase mutation in a family with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Molecular docking, dynamic simulation and computational investigations

“…Based on the results obtained by docking and MD simulation, we can conclude that L402Q caused a conformational change in TP mutated structure and therefore could alter the flexibility and stability of the TP enzyme then prevent the formation of homodimer led to non‐functional protein leading to partial or complete loss of its catalytic activity. This TP dysfunction could lead to the accumulation of both dThd and dUrd in the plasma and the tissues of patients P1 and P2 causing probably nucleoside and nucleotide pool imbalance and then disrupts the equilibrium of intramitochondrial (dNTP) pools (Hammans, 2020; Nishino et al, 2000).…”

“…Consequently, dramatically increased levels of both (dThd) and (dUrd) were detected in MNGIE patients in plasma and in tissues. The increased levels of dThd and dUrd lead to cytidine triphosphate (dCTP) reduction causing the impairment of the nucleotide salvage pathway and the disruption of the intramitochondrial deoxyribonucleoside triphosphate (dNTP) pool equilibrium, which subsequently caused mitochondrial DNA abnormalities in various tissues (Hammans, 2020; Nishino et al, 2000). TP is a cytosolic enzyme composed of two subunit homodimers and is highly expressed in the central and peripheral nervous system, in the gastrointestinal tract, in leukocytes, and in platelets.…”

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

“…This has an effect on post-mitotic tissues that continuously turn over mitochondria and replicate mitochondrial DNA but do not replicate nuclear DNA. The diagnosis of MNGIE can therefore be established by detection of biallelic pathogenic variants in TYMP, markedly reduced levels of thymidine phosphorylase activity, or elevated plasma levels of thymidine and deoxyuridine [ 3 , 6 ].…”

“…MNGIE normally manifests between the first and second decade of life and presents with gastrointestinal dysfunction, excessive weight loss, ptosis, external ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy on MRI [ 6 ]. Gastrointestinal symptoms include dysmotility, pain, discomfort, nausea, intestinal pseudo-obstruction, and bowel diverticulitis [ 7 ].…”