Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine.
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.
Giordano
Carla
C
Dipartimento di Medicina Sperimentale e Patologia, Universita' di Roma La Sapienza, Rome, Italy. carla.giordano@uniroma1.it
Sebastiani
Mariangela
M
Plazzi
Giuseppe
G
Travaglini
Claudia
C
Sale
Patrizio
P
Pinti
Marcello
M
Tancredi
Andrea
A
Liguori
Rocco
R
Montagna
Pasquale
P
Bellan
Marzio
M
Valentino
Maria Lucia
ML
Cossarizza
Andrea
A
Hirano
Michio
M
d'Amati
Giulia
G
Carelli
Valerio
V
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*
D004272:DNA, Mitochondrial; D013939:Thymidine Phosphorylase