Mitochondrial Neurogastrointestinal Encephalomyopathy: Evidence of Mitochondrial DNA Depletion in the Small Intestine

Giordano, Carla; Sebastiani, Mariangela; Plazzi, Giuseppe; Travaglini, C.; Sale, Patrizio; Pinti, Marcello; Tancredi, Andrea; Liguori, Rocco; Montagna, Pasquale; Bellan, Marzio; Valentino, Maria Lucia; Cossarizza, Andrea; Hirano, Michio; d’Amati, Giulia; Carelli, Valerio

doi:10.1053/j.gastro.2006.01.004

Cited by 61 publications

(39 citation statements)

References 20 publications

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“…The morphological and molecular features of cricopharyngeal muscle account for the oropharyngeal dysfunction (dysphagia) observed in MNGIE patients. The selective localization of mtDNA deletions confirms our previous findings in a single MNGIE patient 13 and strengthens the hypothesis that deleted mtDNA molecules accumulate over the years only in postmitotic tissues such as skeletal muscle. 10 In contrast, the load of deleted mtDNA molecules may be reduced in replicating cells because of negative selection.…”

Section: Discussionsupporting

confidence: 90%

“…We recently showed atrophy, mitochondrial proliferation, and mtDNA depletion in muscularis propria of small intestine in one patient. 13 In the present study, we provide a detailed morphological and molecular investigation of the entire GI tract in five MNGIE patients, hence establishing a link between marked mtDNA depletion and myopathic changes of the external layer of muscularis propria in this syndrome.…”

mentioning

confidence: 63%

“…13 Briefly, serial 5-m-thick cut sections were mounted on a polyethylene foil slide and stained with H&E. Sections were observed under light microscope with a ϫ40 objective. Selected tissue areas were microdissected by an UV laser, which performs circumferential dissection, following precisely a drawn incision path.…”

Section: Laser Capture Microdissectionmentioning

confidence: 99%

“…The deletion junctions were as described. 10,13 Analysis of microdissected smooth muscle cells from tunica muscularis and striated muscle cells from cricopharyngeal muscle revealed detectable levels of deleted mtDNA molecules only in striated muscle fibers ( Figure 3D). Attempts to detect mtDNA deletions in single COXpositive and COX-negative cricopharyngeal fibers failed, due to the inability to amplify mtDNA from COX-negative fibers.…”

Section: Molecular Analysis Mtdna Deletionsmentioning

confidence: 99%

“…Noteworthy, even in the control group, we observed a non-homogeneous distribution of mtDNA within the different segments of GI tract; the relative amount of mtDNA in the small intestine was 55% of the level in esophagus, 49% of stomach, and 61% of colon ( Figure 4A), confirming our previous report. 13 Gastrointestinal …”

Section: Mtdna Depletion In Tissue Homogenatesmentioning

confidence: 99%

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Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Giordano

Sebastiani

Giorgio

et al. 2008

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudoobstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall. (Am J Pathol

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 63%

Section: Laser Capture Microdissectionmentioning

confidence: 99%

Section: Molecular Analysis Mtdna Deletionsmentioning

confidence: 99%

Section: Mtdna Depletion In Tissue Homogenatesmentioning

confidence: 99%

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Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Giordano

Sebastiani

Giorgio

et al. 2008

The American Journal of Pathology

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Treatment of Mitochondrial Neurogastrointestinal Encephalomyopathy With Dialysis

Yavûz

Özel²,

Christensen³

et al. 2007

Arch Neurol

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To study the effect of continuous ambulatory peritoneal dialysis on nucleoside levels and clinical course in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).Patient: We studied a patient with genetically verified MNGIE, who prior to treatment had lost weight progressively, developed amenorrhea, vomited multiple times daily, and had abdominal pain. Intervention:The patient was treated with peritoneal dialysis for 3 years, and the effect on symptoms and plasma concentrations of thymidine and deoxyuridine were monitored.Results: Dialysis stopped vomiting and reduced abdominal pain, and the patient gained 5 kg in weight and started to menstruate again. Symptoms returned if dialysis was paused. Dialysis did not affect plasma nucleoside levels. Conclusions:This study shows an unambiguous clinical benefit of peritoneal dialysis on gastrointestinal symptoms in MNGIE. Dialysis did not affect nucleoside levels, indicating elevated thymidine and deoxyuridine levels are not solely responsible for the pathogenesis of MNGIE.

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Hirano

Carelli

Giorgio

et al. 2020

J of Inher Metab Disea

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory

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Mitochondrial Neurogastrointestinal Encephalomyopathy: Evidence of Mitochondrial DNA Depletion in the Small Intestine

Cited by 61 publications

References 20 publications

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Treatment of Mitochondrial Neurogastrointestinal Encephalomyopathy With Dialysis

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

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