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 resume 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.
Highlights
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; Online Mendelian inheritance in Man #603041, Genome Database accession #9835128) is a fatal inherited metabolic disorder caused by mutations in a nuclear gene impacting on the replication and expression of the mitochondrial genome[1,2]
MNGIE is an autosomal recessive disease caused by loss of function mutations in TYMP, a nuclear gene located on chromosome 22 which encodes for thymidine phosphorylase
These perturbations affect the physiological equilibrium of the four deoxyribonucleotides within the mitochondria, thereby interfering with the normal replication of mitochondrial DNA, leading to multiple deletions, somatic point mutations and depletion of mtDNA, and mitochondrial failure[1,9,10,11,12,13,14] [Figure 1]. mtDNA encodes for polypeptides, transfer RNA and ribosomal RNA required for the synthesis of enzymes involved in oxidative phosphorylation
Summary
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; Online Mendelian inheritance in Man #603041, Genome Database accession #9835128) is a fatal inherited metabolic disorder caused by mutations in a nuclear gene impacting on the replication and expression of the mitochondrial genome[1,2]. Pathogenic mutations in TYMP cause a complete or partial deficiency in enzyme activity, which leads to a measurable systemic accumulation of thymidine and 2’-deoxyuridine and, elevated intracellular concentrations of their corresponding triphosphates. These perturbations affect the physiological equilibrium of the four deoxyribonucleotides within the mitochondria, thereby interfering with the normal replication of mitochondrial DNA (mtDNA), leading to multiple deletions, somatic point mutations and depletion of mtDNA, and mitochondrial failure[1,9,10,11,12,13,14] [Figure 1]. The consequent failure of cellular energy production is believed to directly cause the cardinal central clinical manifestations through damage to the nervous and muscular systems
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