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Page 2 Bax. J Transl Genet Genom 2020;4:1-16 I http://dx.doi.org/10.20517/jtgg.2020.08

INTRODUCTION
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; Online Mendelian inheritance in Man
#603041, Genome Database accession #9835128) is a fatal inherited metabolic disorder caused by mutations
[1,2]
in a nuclear gene impacting on the replication and expression of the mitochondrial genome . The
[3]
disorder was first described by Okamura et al. in 1976 as congenital oculoskeletal myopathy. Patients with
ocular, neurological, skeletal and gastrointestinal involvement were subsequently described, with use of the
following nomenclatures: mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia
and pseudo-obstruction (MEPOP); mitochondrial neurogastrointestinal encephalopathy syndrome;
myoneurogastrointestinal encephalopathy syndrome; chronic intestinal pseudo-obstruction with myopathy
and ophthalmoplegia; polyneuropathy, ophthalmoplegia, leukoencephalopathy and intestinal pseudo-
obstruction (POLIP); oculogastrointestinal encephalopathy syndrome; oculogastrointestinal muscular
[4-8]
[9]
dystrophy (OGIDM); and thymidine phosphorylase deficiency . Hirano et al. in 1994 proposed the
current nomenclature, MNGIE, as it precisely describes the key features of this mitochondrial disorder. The
aetiology of MNGIE was later attributed to a deficiency in the enzyme thymidine phosphorylase (Enzyme
[1]
Commission 2.4.2.4) .
MNGIE is an autosomal recessive disease caused by loss of function mutations in TYMP (previously
known as ECGF1), a nuclear gene located on chromosome 22 which encodes for thymidine phosphorylase.
The protein in the past has also been referred to as gliostatin and platelet derived-endothelial cell growth
factor due to its growth inhibitory factor and angiogenic factor activities, respectively. Thymidine
phosphorylase catalyses the reversible phosphorylation of the pyrimidine deoxyribonucleosides, thymidine
(deoxythymidine) and 2’-deoxyuridine to 2-deoxyribose 1-phosphate and their respective bases, thymine
and uracil . Pathogenic mutations in TYMP cause a complete or partial deficiency in enzyme activity,
[1]
which leads to a measurable systemic accumulation of thymidine and 2’-deoxyuridine and, consequently,
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 ultimately mitochondrial failure [1,9-14] [Figure 1]. mtDNA encodes
for polypeptides, transfer RNA and ribosomal RNA required for the synthesis of enzymes involved in
oxidative phosphorylation. 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.

MNGIE is a progressive, multi-system disease, with a characteristic, although by no means universal,
clinical presentation with gastrointestinal symptoms, including early satiety, dysphagia, nausea, chronic
abdominal pain and diarrhoea leading to weight loss. These symptoms are secondary to alimentary
dysmotility caused by degeneration of the alimentary autonomic nervous system. Patients generally have
a thin body habitus with reduced muscle mass and cachexia is common. Episodes of frank intestinal
pseudo-obstruction may occur and some patients develop a hepatopathy with liver steatosis and cirrhosis.
Progressive external ophthalmoplegia and peripheral sensorimotor polyneuropathy are invariable, with
the latter affecting the lower limbs initially. On magnetic resonance imaging (MRI), there is, in most
cases, diffuse increased T2 signal in the cerebral hemispheres but this is usually asymptomatic [2,9,10] . Patient
survival is generally related to the degree of gastrointestinal involvement, with patients dying at an average
age of 37.6 years as a result of cachexia, peritonitis, oesophageal bleeding, intestinal rupture or aspiration
pneumonia [10,15,16] .

MNGIE is an ultra-rare disorder with an estimated European prevalence of 1 in 1,000,000 (Orphanet
report, 2019), although this figure is entirely dependent on evidence reported in the literature and therefore
[17]
cannot be considered absolutely correct . The disease is reported to be widely distributed amongst an
ethnically diverse population including Hispanics, Africans, Americans, Western Europeans, Chinese,