Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Hirano, Michio; Silvestri, Gabriella; Blake, D. M.; Lombès, Anne; Minetti, Carlo; Bonilla, Eduardo; Hays, Arthur P.; Lovelace, Robert E.; Butler, Ian J.; Bertorini, Tulio E.; Threlkeld, Anisa B.; Mitsumoto, Hiroshi; Salberg, Larry M.; Rowland, Lewis P.; DiMauro, Salvatore

doi:10.1212/wnl.44.4.721

Cited by 389 publications

(280 citation statements)

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“…Although MNGIE is well recognized to cause severe gastrointestinal involvement,14, 15 our findings suggest that severe gastrointestinal involvement is much more common overall in m.3243A>G‐related mitochondrial disease. Thirteen percent of our patient cohort presented with severe gastrointestinal dysmotility symptoms with almost one third concomitantly presenting during an acute stroke‐like episode.…”

Section: Discussionmentioning

confidence: 67%

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Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

Feeney

Schaefer

et al. 2016

Annals of Neurology

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ObjectivesThe m.3243A>G MTTL1 mutation is the most common cause of mitochondrial disease; yet there is limited awareness of intestinal pseudo‐obstruction (IPO) in this disorder. We aimed to determine the prevalence, severity, and clinical outcome of patients with m.3243A>G‐related mitochondrial disease manifesting with IPO.MethodsIn this large, observational cohort study, we assessed the clinical, molecular, and radiological characteristics of patients with genetically determined m.3243A>G‐related mitochondrial disease, who presented with severe symptoms suggestive of bowel obstruction in the absence of an occluding lesion.ResultsBetween January 2009 and June 2015, 226 patients harbouring the m.3243A>G mutation were recruited to the Medical Research Council Centre Mitochondrial Disease Patient Cohort, Newcastle. Thirty patients (13%) presented acutely with IPO. Thirteen of these patients had a preceding history of stroke‐like episodes, whereas 1 presented 27 years previously with their first stroke‐like episode. Eight patients developed IPO concomitantly during an acute stroke‐like episode. Regression analysis suggested stroke was the strongest predictor for development of IPO, in addition to cardiomyopathy, low body mass index and high urinary mutation load. Poor clinical outcome was observed in 6 patients who underwent surgical procedures.InterpretationOur findings suggest, in this common mitochondrial disease, that IPO is an under‐recognized, often misdiagnosed clinical entity. Poor clinical outcome associated with stroke and acute surgical intervention highlights the importance of the neurologist having a high index of suspicion, particularly in the acute setting, to instigate timely coordination of appropriate care and management with other specialists. Ann Neurol 2016;80:686–692

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Section: Discussionmentioning

confidence: 67%

“…Although gastrointestinal involvement, manifesting as intestinal pseudo‐obstruction (IPO), has been reported previously 9, 10, 11, 12, 13 and indeed is a recognized feature of the rare neurogastrointestinal encephalopathy (MNGIE) syndrome,14, 15 there remains a limited awareness of the severity of IPO in m.3243A>G‐related mitochondrial disease 16, 17…”

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confidence: 99%

Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

Feeney

Schaefer

et al. 2016

Annals of Neurology

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“…These GI problems lead to extreme weight loss and reduced muscle mass (cachexia). 37,38 It is conceivable that similar functional defects could be involved in the Ant2 hypomorphic animals, and potential contribution of Ant2 mutations in clinical patients with gastroparesis should be a subject for future investigation.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

Seo

et al. 2015

Cell Death Differ

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Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.

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“…Mutations in the mitochondrial proteins adenine nucleotide translocator 1 (ANT1) (Kaukonen et al), Twinkle (Spelbrink et al) and polymerase γ (Van Goethem et al) have been found to cause autosomal dominant progressive external ophthalmoplegia with multiple deletion of mtDNA. Mitochondrial Neurogastrointestinal Encephalomyopathy (MINGIE) is an autosomal recessive disorder due to loss-of-function mutations in the gene encoding thymidine phosphorylase, associated with multiple deletions, depletion and site-specific point mutations of mtDNA (Hirano et al, 1994;Nishigaki et al, 2003;Papadimitriou et al, 1998). ANT1 forms a homodimeric inner mitochondrial membrane channel that translocates ADP into ATP out of the mitochondrial matrix.…”

Section: Causes For Mtdna Depletion and Deletionmentioning

confidence: 99%

Regulation of mitochondrial DNA content and cancer

Higuchi

2007

Mitochondrion

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Enzymatic activities of the proteins encoded in nuclear genome are regulated by transcriptional, translational and post-transcriptional level. Enzymatic activities of proteins encoded in mitochondrial DNA (mtDNA) have been considered to be regulated by the same steps although detailed mechanisms might differ. However, dynamic change of the number of mtDNA, from some hundred to more than ten thousand, should be considered as another novel mechanism to regulate mtDNA-encoded proteins. Recently, we showed the connection of mtDNA depletion and deletion to cancer progression (Higuchi et al., 2006). This review focuses and describes the possible connections of the mitochondrial DNA depletion and deletion to cancer.

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Cited by 389 publications

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Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

Regulation of mitochondrial DNA content and cancer

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