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mitochondrial neurogastrointestinal encephalomyopathy

MIM.603041

Saturday 28 November 2009

Myoneurogastrointestinal encephalopathy, or mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), is an autosomal recessive progressive multisystem disorder clinically characterized by onset between the second and fifth decades of life of ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction (Taanman et al., 2009).

Synopsis

- mitochondrial-neuro-gastro-intestinal encephalomyopathy (MNGIE) (pseudo-obstruction-leukoencephalopathy-intestinal-pseudoobstruction syndrome) [POLIP])

  • It is a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms.
  • This condition was associated with
    • (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%);
    • (b) a CIPO syndrome with the presence of small bowel diverticulae (53%);
    • (c) mitochondrial cytopathy and thymidine phosphorylase gene mutations

Etiology

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome can be caused by mutations in the gene encoding thymidine phosphorylase (TYMP; MIM.131222).

A form of MNGIE without leukoencephalopathy can be caused by a mutation in the DNA polymerase gamma gene (POLG; MIM.174763).

One patient with a clinical phenotype overlapping that of MNGIE has been reported with mutations in the RRM2B gene (MIML604712).

The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s).

Mitochondrial abnormalities are evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells.

See also

- familial visceral myopathy with external ophthalmoplegia (MIM.277320)
- intestinal pseudoobstruction due to neuronal disease (MIM.243180)

References

- Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M. Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum. Molec. Genet. 18: 714-722, 2009. [PubMed: 19028666]

- Digestive smooth muscle mitochondrial myopathy in patients with mitochondrial-neuro-gastro-intestinal encephalomyopathy (MNGIE). Blondon H, Polivka M, Joly F, Flourie B, Mikol J, Messing B. Gastroenterol Clin Biol. 2005 Aug-Sep;29(8-9):773-8. PMID: 16294144

- Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation. J. Med. Genet. 41: 125-129, 2004. [PubMed: 14757860]

- Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M. Phenotypic variability in a Spanish family with MNGIE. Neurology 59: 455-457, 2002. [PubMed: 12177387]

- Hagiwara, K., Stenman, G., Honda, H., Sahlin, P., Andersson, A., Miyazono, K., Heldin, C. H., Ishikawa, F., Takaku, F. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene. Molec. Cell. Biol. 11: 2125-2132, 1991. [PubMed: 2005900]

- Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Molec. Cell. Biol. 22: 5212-5221, 2002. [PubMed: 12077348]

- Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. Late-onset MNGIE due to partial loss of thymidine phosphorylase activity. Ann. Neurol. 58: 649-652, 2005. [PubMed: 16178026]

- Nishino, I., Spinazzola, A., Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283: 689-692, 1999. [PubMed: 9924029]

- Stenman, G., Sahlin, P., Dumanski, J. P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V. P., Heldin, C.-H. Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13. Cytogenet. Cell Genet. 59: 22-23, 1992. [PubMed: 1733667]