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Review
. 2018 Dec 21:9:669.
doi: 10.3389/fgene.2018.00669. eCollection 2018.

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Dario Pacitti  1 , Michelle Levene  1 , Caterina Garone  2 , Niranjanan Nirmalananthan  3 , Bridget E Bax  1
Affiliations
Review

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Dario Pacitti et al. Front Genet. .

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

Keywords: MNGIE; TYMP; deoxyribonucleoside; mitochondrial DNA; mitochondrial disease; mitochondrial neurogastrointestinal encephalomyopathy; rare disease; thymidine phosphorylase.

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Figures

Figure 1
Figure 1
Reactions catalysed by thymidine phosphorylase.
Figure 2
Figure 2
Deoxynucleotide salvage and de-novo synthesis pathways. Abbreviations are as follows: deoxythymidine (dThd), deoxyuridine (dUrd), deoxythymidine monophosphate (dTMP), deoxythymidine diphosphate (dTDP), deoxynucleotidase 1 (dNT1), thymidine phosphorylase (TP), thymidine kinase 1 (TK1), deoxynucleotidase 2 (dNT2), nucleotide monophosphate kinase (NMPK), nucleotide diphosphate kinase (NDPK), deoxythymidine triphosphate (dTTP), thymidine kinase 2 (TK2), DNA polymerase Y (DNA pol Y), nucleotide diphosphate (NDP), ribonucleotide reductase (RNR), deoxyribonucleotide diphosphate (dNDP), and deoxynucleotide triphosphate (dNTP).
Figure 3
Figure 3
Metabolic defect in MNGIE.
Figure 4
Figure 4
Pathogenic TYMP gene mutations (NM_001113755.2; NP_001107227) in exonic and intronic regions. Protein changes, where known are indicated in red font.
Figure 5
Figure 5
Major clinical features of MNGIE. Copyright permission was obtained for the reproduction of images taken from Bariş et al. (2010), Filosto et al. (2011), Scarpelli et al. (2012).
Figure 6
Figure 6
Mechanism of EE-TP action. Plasma thymidine and deoxyuridine enter the erythrocyte via nucleoside transports located in the cell membrane, where the encapsulated thymidine phosphorylase catalyses their metabolism to thymine and uracil. The products are then free to diffuse out of the cell into the blood plasma where they can enter the normal metabolic pathways.
Figure 7
Figure 7
Timeline of pre-clinical and clinical investigational therapeutic approaches for MNGIE.
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