title: Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine.
abstract: OBJECTIVE
  Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE.
  
  
  METHODS
  By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls.
  
  
  RESULTS
  The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA.
  
  
  CONCLUSIONS
  Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient.
authors.affiliation: Dipartimento di Medicina Sperimentale e Patologia, Universita' di Roma La Sapienza, Rome, Italy. carla.giordano@uniroma1.it
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sebastiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Travaglini
authors.forename: Patrizio
authors.initials: P
authors.lastname: Sale
authors.forename: Marcello
authors.initials: M
authors.lastname: Pinti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tancredi
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Pasquale
authors.initials: P
authors.lastname: Montagna
authors.forename: Marzio
authors.initials: M
authors.lastname: Bellan
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D002100:Cachexia / Q000235:genetics* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D005767:Gastrointestinal Diseases / Q000235:genetics*; D005769:Gastrointestinal Motility / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008297:Male; D042282:Microdissection; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D013939:Thymidine Phosphorylase / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D013939:Thymidine Phosphorylase