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).

OBJECTIVE: A nationwide survey was conducted to identify the clinical presentation of pediatric chronic intestinal pseudo-obstruction (CIPO) in Japan.
METHODS: Data were collected via a questionnaire, ensuring patient anonymity, from facilities that treat pediatric gastrointestinal diseases in Japan.
RESULTS: Ninety-two responses were collected from forty-seven facilities. Sixty-two patients (28 males, 34 females) met formal diagnostic criteria for CIPO. The estimated pediatric prevalence was 3.7 in 1 million individuals. More than half the children (56.5%) developed CIPO in the neonatal period. Full-thickness intestinal specimens were available for histopathology assessment in forty-five patients (72.6%). Forty-one (91.1%) had no pathological abnormalities and were considered to be idiopathic. Patients were treated according to the local protocol of each facility. Forty-one patients (66.1%) had restricted oral intake of ordinary diets, and twenty-nine (46.8%) depended on parenteral nutrition. No therapeutic intervention, including medication and surgery, successfully improved oral food intake or obstructive symptoms. Only three patients (4.8%) died from enteritis or sepsis.
CONCLUSIONS: In Japan, pediatric CIPO is a rare, serious, and intractable disease. The prognosis with respect to survival is good, but unsatisfactory because of the need for prolonged parenteral nutrition and associated potential for restricted quality of life.