Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype-phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first \'European Forum on Visceral Myopathy\'. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy.

UNASSIGNED: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project.
UNASSIGNED: We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in ACTG2, ACTA2, MYH11, MYLK, LMOD1, CHRM3, MYL9, FLNA and KNCMA1 by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort.
UNASSIGNED: We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in KCNMA1 which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 variants as the largest contributor to VM-related phenotypes.
UNASSIGNED: VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified ACTG2 as the most frequent genetic cause of VM. We recommend a nomenclature change to \'autosomal dominant ACTG2 visceral myopathy\' for patients with pathogenic variants in ACTG2 and associated VM phenotypes.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s44162-023-00012-z.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is present in the ACTG2 gene. Here, we aimed to investigate the pathogenesis of ACTG2 in MMIHS.
A cohort with 20 patients with MMIHS was screened. Actg2R257C heterozygous mutant mice were generated using the CRISPR/Cas9 system. Gastrointestinal (GI) motility, voluntary urination, collagen gel contraction, and G-actin/F-actin analysis were performed.
The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2R257C heterozygous mutant mice had dilated intestines and bladders. The functional assay showed a prolonged total time of GI transit and decreased urine spot area. Collagen gel contraction assay and G-actin/F-actin analysis indicated that mutant mice showed reduced area of contraction of smooth muscle cells (SMCs) and impaired actin polymerization.
A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2R257C heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.

Smooth muscle disorders affecting both the intestine and the bladder have been known for a decade. However, the recent discovery of genes associated with these dysfunctions has led to the description of several clinical phenotypes. We performed a systematic review of all published cases involving seven genes with pathogenic variants, ACTG2, MYH11, FLNA, MYLK, RAD21, MYL9 and LMOD1, and included 28 articles describing 112 patients and 5 pregnancies terminated before birth. The most commonly described mutations involved ACTG2 (75/112, 67% of patients), MYH11 (14%) and FLNA (13%). Twenty-seven patients (28%) died at a median age of 14.5 months. Among the 76 patients for whom this information was available, 10 (13%) had isolated chronic intestinal pseudo-obstruction (CIPO), 17 (22%) had isolated megacystis, and 48 (63%) had combined CIPO and megacystis. The respective proportions of these phenotypes were 9%, 20% and 71% among the 56 patients with ACTG2 mutations, 20%, 20% and 60% among the 10 patients with MYH11 mutations and 50%, 50% and 0% among the 7 patients with FLNA mutations.

BACKGROUND: Dominant gamma-smooth muscle actin gene (ACTG2) variants cause clinically diverse forms of visceral myopathy. Many patients undergo intestinal resection or biopsy before identification of their genetic defect. The pathology of ACTG2-variant visceral myopathy has not been evaluated systematically.
METHODS: Glass slides, ultrastructural images, molecular genetic reports, and clinical records from 16 patients with pathogenic (15) or likely pathogenic (1) ACTG2 variants were reviewed and compared with surgical specimens from controls (no evidence of a primary myopathy or pseudo-obstruction due to Hirschsprung disease) and published descriptions.
RESULTS: The variable clinical manifestations in our cohort matched those in the literature. Only non-specific light and electron microscopic findings observed in non-myopathic controls were encountered in 13 of 16 patients. The remaining 3 patients harbored hyalinized cytoplasmic inclusions in smooth muscle cells and 1 of them had polyglucosan bodies in the muscularis propria.
CONCLUSIONS: Apart from hyalinized inclusions, which were only observed in 3/16 patients, intestinal pathology in the majority of patients with ACTG2 variants is not indicative of an underlying visceral myopathy. Molecular testing should be considered even when no diagnostic intestinal pathology is identified.

Background Phenotypic switching in vascular smooth muscle cells (VSMCs) is involved in the pathogenesis of aortic dissection (AD). This study aims to explore the potential mechanisms of linc01278 during VSMC phenotypic switching. Methods and Results Twelve samples (6 AD and 6 control) were used for lncRNA, microRNA, and mRNA microarray analysis. We integrated the mRNA microarray data set with GSE52093 to determine the differentially expressed genes. Bioinformatic analysis, including Gene Expression Omnibus 2R, Venn diagram analysis, gene ontology, pathway enrichment, and protein-protein interaction networks were used to identify the target lncRNA, microRNA, and mRNA involved in AD. Subsequently, we validated the bioinformatics data using techniques in molecular biology in human tissues and VSMCs. Linc01278, microRNA-500b-5p, and ACTG2 played an important role in the vascular smooth muscle contraction pathway. Linc01278 and ACTG2 were downregulated and miR-500b-5p was upregulated in AD tissues. Molecular markers of VSMC phenotypic switching, including SM22α, SMA, calponin, and MYH11, were downregulated in AD tissues. Plasmid-based overexpression and RNA interference-mediated downregulation of linc01278 weakened and enhanced VSMC proliferation and phenotypic switching, respectively. Dual-luciferase reporter assays confirmed that linc01278 regulated miR-500b-5p that directly targeted ACTG2 in HEK293T cells. Conclusions These data demonstrate that linc01278 regulates ACTG2 to control the phenotypic switch in VSMCs by sponging miR-500b-5p. This linc01278-miR-500b-5p-ACTG2 axis has a potential role in developing diagnostic markers and therapeutic targets for AD.

Visceral myopathy is a rare genetic disorder that commonly affects the digestive and renal systems. Manifestations include a clinical spectrum covering chronic intestinal pseudo-obstruction (CIPO) and megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). The smooth muscle actin γ-2 gene (ACTG2) is one of the most common disease-causing genes. Here, we present a case of pediatric intestinal pseudo-obstruction associated with a novel missense ACTG2 mutation, c.588G>C/p.E196D. His parents had no this mutation, which suggested the possibility of spontaneous mutation. Amino acid conservation analysis of γ-2 actin showed replacement of glutamate at position 196 by aspartate. The patient suffered from recurrent episodes of abdominal bloating, undergone repeated gastrointestinal surgery, had feeding difficulties, and required long-term parenteral nutrition support. The patient had no other specific symptoms or underlying diseases. X-ray of the abdomen showed dilation of the intestine as well as an air-fluid pattern. The manifestations of biopsy were various. All biochemical tests were normal, and the possibility of secondary intestinal pseudo-obstruction was excluded. The mutation site of ACTG2 in the present study has not been previously described in patients with visceral myopathy, and thus, our study reveals a novel mutation of ACTG2-associated visceral myopathy in a patient with CIPO. This report can serve as a reference for future research and further expands the map of genetic variation for visceral myopathy.

Eosinophilic esophagitis (EoE) is a chronic, food antigen-mediated disease characterized by esophageal dysfunction and intraepithelial eosinophil accumulation.
We hypothesized that very early onset EoE (V-EoE) would be enriched for early-life and genetic factors and have worse presentation and prognosis than later-onset pediatric EoE (L-EoE).
We conducted a single-site, retrospective review comparing patients diagnosed at age 12 months or less (V-EoE, n = 57) and age 14 to 18 years (L-EoE, n = 70). These patients underwent medical record, EoE Histology Scoring System, Endoscopic Reference Score, and EoE Diagnostic Panel assessment when sample availability permitted. Genetic association used 2 EoE genotype repositories. Data were analyzed using chi-square tests, t tests, Wilcoxon rank-sum tests, Spearman correlations, cluster analysis, and logistic regression.
Among pediatric patients with EoE, diagnosis most commonly occurred within early life (0-24 months, 17%). V-EoE was more likely to attain histologic remission via dietary restriction (P < .0001). Basal zone hyperplasia and eosinophil inflammation were greater in V-EoE (P < .05). Esophageal strictures more commonly occurred in L-EoE (P = .03). V-EoE had lower endoscopic scores (P < .05). Molecular expression was very similar between groups. Cesarean delivery was more common in patients with V-EoE (P = .03). Patients with V-EoE demonstrated enrichment of CAPN14 common genetic variants.
Early-life diagnosis of EoE is a common occurrence. V-EoE responds to standard therapy without early evidence for complications, suggesting a less severe prognosis than hypothesized. Molecular pathogenesis is preserved between V-EoE and L-EoE. Cesarean delivery and CAPN14 genetic variation likely promote earlier disease development.

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

The purpose of this overview is to increase the awareness of clinicians regarding megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and its genetic causes and management. The following are the goals of this overview. GOAL 1: Describe the clinical characteristics of MMIHS. GOAL 2: Review the genetic causes of MMIHS. GOAL 3: Provide an evaluation strategy to identify the genetic cause of MMIHS in a proband (when possible). GOAL 4: Inform genetic counseling of family members of an individual with MMIHS. GOAL 5: Review management of MMIHS.