Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations

Nishino, Ichizo; Spinazzola, Antonella; Papadimitriou, Alexandros; Hammans, Simon; Steiner, Israel; Hahn, Cecil D.; Connolly, Anne M.; Verloes, Alain; Guimarães, João Tiago; Maillard, Ivan; Hamano, Hitoshi; Donati, M. A.; Semrad, Carol E.; Russell, James A.; Andreu, Antonio Lorenzo; Hadjigeorgiou, Giorgos M.; Vu, Tuan; Tadesse, Saba; Nygaard, Torbjoern G.; Nonaka, Ikuya; Hirano, Ikuo; Bonilla, Eduardo; Rowland, Lewis P.; DiMauro, Salvatore; Hirano, Michio

doi:10.1002/1531-8249(200006)47:6<792::aid-ana12>3.3.co;2-p

Cited by 32 publications

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“…Our finding expands the clinical spectrum of recessive POLG mutations since severe gastrointestinal features caused by dysmotility and dilation have not been encountered previously in recessive PEO patients with POLG mutations 5,6 while they are prominent manifestations of MNGIE caused by TP mutations. 8,11 The more severe phenotype in the present family versus previously described recessive PEO patients with POLG mutations might result from a greater functional impairment of POLG induced by the three mutations together. Also, depending on the location of the mutation within POLG a more or less severe effect on POLG functioning may result.…”

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confidence: 64%

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Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

et al. 2003

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Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.

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confidence: 64%

“…Various laboratory findings are reported, including leukoencephalopathy on brain MRI. 8 Here, we report the finding of recessive missense mutations in POLG in two sisters with a clinical phenotype undistinguishable from MNGIE.…”

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confidence: 71%

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

et al. 2003

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“…6 Among mitochondrial encephalomyopathies, one most frequently associated with GI dysmotility and CIPO is mitochondrial neurogastrointestinal en-cephalomyopathy (MNGIE), an autosomal recessive syndrome due to mutations in the thymidine phosphorylase gene TYMP. 7 MNGIE is defined clinically by severe GI dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. 7 GI dysmotility leads to progressive weight loss and cachexia of MNGIE patients, and diverticulosis of small intestine complicated by inflammation and perforation often causes their death in early adulthood.…”

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confidence: 99%

“…7 MNGIE is defined clinically by severe GI dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. 7 GI dysmotility leads to progressive weight loss and cachexia of MNGIE patients, and diverticulosis of small intestine complicated by inflammation and perforation often causes their death in early adulthood. Biochemical abnormalities in MNGIE include drastically reduced thymidine phosphorylase activity leading to accumulation of thymidine (dThd) and deoxyuridine (dUrd) in blood and tissues.…”

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confidence: 99%

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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“…This enzyme catalyses phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. 3 For this reason, MNGIE patients show increased levels of thymidine in plasma and urine. The gene has been cloned and mapped by Nishino et al in 1999.…”

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confidence: 99%

Pre‐ and post‐dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC‐ESI‐MS/MS

Marca

Malvagia

Casetta³

et al. 2006

J. Mass Spectrom.

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. The disease is due to a thymidine phosphorylase defect. This enzyme catalyses the phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. For this reason, increased levels of thymidine in plasma and urine are found in MNGIE patients. Haemodialysis can reduce circulating plasma thymidine levels and can be beneficial in some MNGIE patients. We developed a fast analytical method based on HPLC-ESI-MS/MS capable of identifying pyrimidine nucleotides (thymine, cytosine, uracil) and nucleosides (thymidine, citidine, uridine) in plasma and urine after direct dilution of the samples without pre-treatment.In the patient studied, we observed a significant reduction of plasmatic and urinary thymidine levels during and after dialysis. However, we noted a progressive reduction of the initial thymidine level after some dialytic trials. This method will be useful not only for thymidine level follow-up during dialysis in MNGIE patients but also for the improvement of the diagnosis or diagnostic suspect in other pyrimidine defects such as dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinase deficiency and ureidopropionase deficiency.

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Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations

Cited by 32 publications

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Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

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

Pre‐ and post‐dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC‐ESI‐MS/MS

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