pediatric CIPO

Pathophysiology

The pathophysiology of childhood chronic intestinal pseudo-obstruction is poorly understood.

The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities.

Several anomalies of the enteric nervous system (ENS) have been described:
 Hirschsprung disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon.
 Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility.
 Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO).

Mitochondrial respiratory chain anomalies

Considering the possible links between mitochondrial respiratory chain activity and digestive tract motility disorders, some investigated the respiratory chain activities in colon and small bowel of a series of CIPO children. (20879992)

None of the 8 children tested by Galmiche et al. harbored a respiratory chain enzyme deficiency, regardless of the smooth muscle (colon, small bowel) or the preparation tested (homogenates or mitochondria-enriched fractions). (20879992)

It is worth noting also that elevated enzyme activities were found in 2/3 myogenic CIPO patients. This increased respiratory chain enzyme activities could be regarded as an adaptive mechanism to a motor defect of the gut wall via accumulation of mitochondria. (20879992)

Although no mitochondrial accumulation in smooth muscle cells could be detected by standard microscopy, one cannot exclude that subtle anomalies could be detected by further morphological explorations.

Brain imaging did not show evocative pattern of mitochondrial disorders as leukoencephalopathy or hypersignal of basal ganglia with lactate peak.

One patient of this series presented with nonspecific posterior white matter abnormalities which are very insufficient for a diagnosis of mitochondrial disorder. Moreover, we did not found mutation in TYMP, POLG, mtDNA tRNA leu(UUR) and tRNAlys genes. (20879992)

PTEN

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation and cell death.

A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development.

Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon.

There is a marked reduction of Pten expression in the myenteric and submucous plexuses of IND patients.

Neuronal Pten deficiency in IND may disrupt the chemical pathway associated with the proliferation and development of neuronal cells forming mature ganglia and thus cause motility dysfunction.

See also

 adult CIPO (adult chronic intestinal pseudo-obstruction)

References

 A role for Pten in paediatric intestinal dysmotility disorders. O’Donnell AM, Puri P. Pediatr Surg Int. 2011 May;27(5):491-3. PMID: 21258937

 Normal oxidative phosphorylation in intestinal smooth muscle of childhood chronic intestinal pseudo-obstruction. Galmiche L, Jaubert F, Sauvat F, Sarnacki S, Goulet O, Assouline Z, Vedrenne V, Lebre AS, Boddaert N, Brousse N, Chrétien D, Munnich A, Rötig A. Neurogastroenterol Motil. 2011 Jan;23(1):24-9. PMID: 20879992