A 42-year-old woman presented at our hospital with acute paraphasia and word finding difficulty. She was not paralyzed or ataxic. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) was diagnosed based on brain MRI finding of edematous lesions in bilateral temporal lobe cortexes that did not match the vascular territory, elevated lactate and pyruvate levels in blood and cerebrospinal fluid, and the presence of a mtDNA 3243A>G mutation. From six months before her visit, she had persistent anorexia, bloating, nausea and vomiting, and weight loss to 25 kg. We diagnosed her condition as chronic intestinal pseudo-obstruction (CIPO) associated with MELAS, because a gastroenterologist had previously diagnosed her with megacolon associated with colonic dysfunction. Usually, CIPO is often associated with the chronic phase of MELAS. However, since CIPO complication from the early stage of the disease is occasionally encountered, it is necessary to include mitochondrial disease in differential diagnosis of CIPO of unknown cause.

Chronic Intestinal Pseudo-obstruction (CIPO) is a rare but debilitating and severe form of gastrointestinal dysmotility. The diagnosis is often made very late in the disease course due to its rarity and complexity. Treatment is mainly supportive, as there is no definitive cure. Pharmacologic therapy comprises prokinetics, antibiotics for bacterial overgrowth and pain management. Pain can also be alleviated with intestinal decompression in selected cases. Beside the pharmacologic therapy, nutrition and fluid replacement play a key role. Rarely, intestinal transplantation is necessary in patients with CIPO and intestinal failure. In this review, we describe an advanced CIPO case and provide an update of the clinical and diagnostic features and current management strategies. The goal of our review is to raise awareness around CIPO and to give practical guidance for the clinician.

BACKGROUND: Intestinal pseudo obstruction both acute and chronic is an uncommon severe motility disorder that affect both children and adults, can lead to significant morbidity burden and have no standard management strategy. Prucalopride a highly selective serotonin receptor agonist is an effective laxative with reported extra colon action. We aim to report our experience in children with acute and chronic intestinal pseudo obstruction who responded to prucalopride and systemically review the use of prucalopride in intestinal pseudo obstruction.
METHODS: A report of clinical experience and systemic review of the relevant medical databases to identify the outcome of usage of prucalopride in patients with acute and chronic intestinal pseudo obstruction. Studies meeting the selection criteria were reviewed including abstract only and case reports.
RESULTS: All reported cases showed clinical response to prucalopride. There were three full text, two abstracts only and three case reports all reporting clinical improvement with prucalopride.
CONCLUSIONS: Prucalopride appears to show promising results in children and adults with acute and chronic intestinal pseudo obstruction.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.

Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome associated with significant mortality and morbidity. It mimics the signs and symptoms of intestinal obstruction in the absence of an anatomic lesion causing obstruction. Here we present a case of a young male with severe alcohol abuse disorder who initially presented with signs and symptoms of alcohol withdrawal but was found to have abdominal distension. Imaging studies revealed severe small and large bowel dilatation without any organic lesion. He continued to have marked intestinal dilatation for the subsequent few months. Alcohol cessation eventually led to a marked reduction in his symptoms and a decrease in intestinal dilatation. The occurrence of CIPO because of alcohol abuse is rare, and we explore the possible association between the two entities.

Visceral smooth muscle is a crucial component of the walls of hollow organs like the gut, bladder, and uterus. This specialized smooth muscle has unique properties that distinguish it from other muscle types and facilitate robust dilation and contraction. Visceral myopathies are diseases where severe visceral smooth muscle dysfunction prevents efficient movement of air and nutrients through the bowel, impairs bladder emptying, and affects normal uterine contraction and relaxation, particularly during pregnancy. Disease severity exists along a spectrum. The most debilitating defects cause highly dysfunctional bowel, reduced intrauterine colon growth (microcolon), and bladder-emptying defects requiring catheterization, a condition called megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). People with MMIHS often die early in childhood. When the bowel is the main organ affected and microcolon is absent, the condition is known as myopathic chronic intestinal pseudo-obstruction (CIPO). Visceral myopathies like MMIHS and myopathic CIPO are most commonly caused by mutations in contractile apparatus cytoskeletal proteins. Here, we review visceral myopathy-causing mutations and normal functions of these disease-associated proteins. We propose molecular, cellular, and tissue-level models that may explain clinical and histopathological features of visceral myopathy and hope these observations prompt new mechanistic studies.

Chronic small bowel pseudo-obstruction is rare, and the disease process is poorly understood. Its clinical picture and radiographic findings can resemble mechanical small bowel obstruction and may lead to unnecessary surgery. We report a case of a 68-year-old man who presented acutely with severe abdominal distension and pain after a recent laparoscopic adhesiolysis. His abdominal CT scan revealed grossly distended small bowel with pneumatosis intestinalis and free intraperitoneal air, which led to an exploratory laparotomy. He had a history of having undergone numerous radiological and endoscopic investigations and multiple laparotomies/laparoscopic procedures but without a definitive diagnosis. Subsequent episodes of small bowel pseudo-obstruction occurred, and he developed intestinal failure. His care required the input of multiple healthcare professionals. He was ultimately referred to the National Intestinal Failure Unit for further assessment and management.

MNGIE is a rare and fatal disease in which absence of the enzyme thymidine phosphorylase induces systemic accumulation of thymidine and deoxyuridine and secondary mitochondrial DNA alterations. Gastrointestinal (GI) symptoms are frequently reported in MNGIE patients, however, they are not resolved with the current treatment interventions. Recently, our understanding of the GI pathology has increased, which rationalizes the pursuit of more targeted therapeutic strategies. In particular, interstitial cells of Cajal (ICC) play key roles in GI physiology and are involved in the pathogenesis of the GI dysmotility. However, understanding of the triggers of ICC deficits in MNGIE is lacking. Herein, we review the current knowledge about the pathology of GI dysmotility in MNGIE, discuss potential mechanisms in relation to ICC loss/dysfunction, remark on the limited contribution of the current treatments, and propose intervention strategies to overcome ICC deficits. Finally, we address the advances and new research avenues offered by organoids and tissue engineering technologies, and propose schemes to implement to further our understanding of the GI pathology and utility in regenerative and personalized medicine in MNGIE.
Interstitial cells of Cajal play key roles in the physiology of the gastrointestinal motility. Evaluation of their status in the GI dysmotility related to MNGIE would be valuable for diagnosis of MNGIE. Understanding the underlying pathological and molecular mechanisms affecting ICC is an asset for the development of targeted prevention and treatment strategies for the GI dysmotility related to MNGIE.

Primary visceral myopathy caused by a pathogenic mutation in the gene encoding the enteric smooth muscle actin gamma 2 ( ACTG2) affects gastrointestinal and genitourinary tracts and often presents as chronic intestinal pseudoobstruction. We present a case of pediatric onset chronic intestinal pseudoobstruction associated with a novel missense ACTG2 mutation c.439G>T/p.G147C. In addition to the known disease manifestations of feeding intolerance and intestinal malrotation, our patient had a late-onset hypertrophic pyloric stenosis and a late-onset choledochal cyst, the former of which has not previously been described in patients with ACTG2-associated visceral myopathy.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is an intractable rare digestive disease manifesting persistent small bowel distension without any mechanical cause. Intestinal decompression is a key treatment, but conventional method including a trans-nasal small intestinal tube is invasive and painful. Therefore, a less invasive and tolerable new decompression method is urgently desired. We conducted a pilot study and assessed the efficacy and safety of percutaneous endoscopic gastro-jejunostomy (PEG-J) decompression therapy in CIPO patients.
METHODS: Seven definitive CIPO patients (2 males and 5 females) were enrolled. All patients received PEG-J decompression therapy. The number of days with any abdominal symptoms in a month (NODASIM), body mass index (BMI), serum albumin level (Alb), and small intestinal volume before and after PEG-J were compared in all patients.
RESULTS: Percutaneous endoscopic gastro-jejunostomy was well tolerated and oral intake improved in all patients. NODASIM has significantly decreased (24.3 vs 9.3 days/months) and BMI/Alb have significantly increased (14.9 vs 17.2 kg/m2 and 2.6 vs 3.8 g/dL, respectively), whereas total volume of the small intestine has not significantly reduced (4.05 vs 2.59 L, P=.18). Reflux esophagitis and chemical dermatitis were observed in one case but was successfully treated conservatively.
CONCLUSIONS: Percutaneous endoscopic gastro-jejunostomy decompression therapy can contribute greatly to improvement of abdominal symptoms and nutritional status in CIPO patients. Although sufficient attention should be paid to acid reflux symptoms, PEG-J has the potential to be a non-invasive novel decompression therapy for CIPO available at home. However, accumulation of more CIPO patients and long-term observation are needed (UMIN000017574).