Intestinal Pseudo-Obstruction

Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase (nNOS-/-) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS+ neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS-/- colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model.

BackgroundWe estimated the prevalence and incidence of chronic intestinal pseudo-obstruction (CIPO) in Japan, investigated the patterns of hospital visits among those with CIPO, and examined present knowledge of CIPO among medical professionals.MethodsA self-administered questionnaire survey was distributed to targeted hospitals throughout Japan, which were selected using stratified random sampling. The questionnaire asked about the number of patients receiving treatment for CIPO, the frequency of their hospital visits, and overall clinical knowledge of CIPO among medical professionals.ResultsCIPO prevalence was estimated to be 1.00 and 0.80 cases per 100 000 males and females, respectively. Incidence was 0.21 and 0.24 cases per 100 000 males and females, respectively. Prevalence and incidence did not significantly differ males and females. Mean age of patients was 63.1 years for males and 59.2 for females. Accurate diagnosis of CIPO sometimes required more than 3 months after initial presentation. Most medical professionals were unaware of or poorly understood CIPO.ConclusionsWe estimated the prevalence and incidence of CIPO in Japan, using data from a nationwide survey. The findings suggest that knowledge of CIPO should be further disseminated so that the disease is not overlooked and is diagnosed without delay.

ObjectivesThe m.3243A>G MTTL1 mutation is the most common cause of mitochondrial disease; yet there is limited awareness of intestinal pseudo-obstruction (IPO) in this disorder. We aimed to determine the prevalence, severity, and clinical outcome of patients with m.3243A>G-related mitochondrial disease manifesting with IPO.MethodsIn this large, observational cohort study, we assessed the clinical, molecular, and radiological characteristics of patients with genetically determined m.3243A>G-related mitochondrial disease, who presented with severe symptoms suggestive of bowel obstruction in the absence of an occluding lesion.ResultsBetween January 2009 and June 2015, 226 patients harbouring the m.3243A>G mutation were recruited to the Medical Research Council Centre Mitochondrial Disease Patient Cohort, Newcastle. Thirty patients (13%) presented acutely with IPO. Thirteen of these patients had a preceding history of stroke-like episodes, whereas 1 presented 27 years previously with their first stroke-like episode. Eight patients developed IPO concomitantly during an acute stroke-like episode. Regression analysis suggested stroke was the strongest predictor for development of IPO, in addition to cardiomyopathy, low body mass index and high urinary mutation load. Poor clinical outcome was observed in 6 patients who underwent surgical procedures.InterpretationOur findings suggest, in this common mitochondrial disease, that IPO is an under-recognized, often misdiagnosed clinical entity. Poor clinical outcome associated with stroke and acute surgical intervention highlights the importance of the neurologist having a high index of suspicion, particularly in the acute setting, to instigate timely coordination of appropriate care and management with other specialists. Ann Neurol 2016;80:686-692.

ObjectivesPediatric intestinal pseudo-obstruction (PIPO) is a severe bowel motility disorder characterized by impaired propulsion of gastrointestinal contents without mechanical obstruction. PIPO encompasses congenital and acquired disorders, including neuropathies, myopathies, and mesenchymopathies. PIPO presents with abdominal distension, bilious vomiting, and severe constipation. Diagnosis is based on objective measures of neuromuscular dysfunction, dilated bowel on imaging, parenteral and/or enteral nutrition dependence, and genetic or metabolic testing. Antroduodenal manometry permits objective assessment of proximal bowel neuromuscular function. Genetic testing is increasingly valuable although causes of PIPO often remain incompletely defined. Understanding genotype-phenotype correlations is essential for clarifying disease mechanisms and guiding therapies. This study aimed to characterize the clinical and genetic profiles of children with PIPO, utilizing manometric data for subtype classification.MethodsA retrospective chart review was conducted at a tertiary care pediatric medical center, with inclusion criteria of PIPO diagnosis, completed manometry testing, and genetic evaluation.ResultsNineteen children met inclusion criteria. Antroduodenal manometry classified 59% as neuropathic, 35% as myopathic, and one with mixed neuropathic and myopathic dysfunction. Genetic testing revealed pathogenic ACTG2 mutations in all myopathic cases, while neuropathic PIPO exhibited more genetic variability. Histopathology was inconsistent and often nonspecific. Therapeutic approaches focused on nutritional support and promotility agents, with surgical intervention more common in myopathic cases.ConclusionsThis study highlights the association of ACTG2 mutations with a myopathic phenotype, and genetic diversity in neuropathic PIPO, emphasizing the need for further research to improve phenotyping to enhance diagnosis and treatment.