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Neurogastroenterology and Motility Jan 2023Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare and serious congenital disorder with poor outcomes, where a heterozygous missense mutation is...
BACKGROUND
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.
METHODS
A cohort with 20 patients with MMIHS was screened. Actg2 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.
KEY RESULTS
The R257C variant of ACTG2 most frequently occurred in patients with MMIHS and demonstrated the typical symptoms of MMIHS. Actg2 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.
CONCLUSIONS & INFERENCES
A mouse model demonstrating MMIHS-like symptoms was generated. The Actg2 heterozygous variant impairs SMCs contraction by interfering with actin polymerization, leading to GI motility disorders.
Topics: Animals; Mice; Abnormalities, Multiple; Actins; Colon; Intestinal Pseudo-Obstruction; Phenotype; Humans
PubMed: 36264152
DOI: 10.1111/nmo.14472 -
BMC Pediatrics Oct 2022Microcolon helps diagnose small bowel atresia (SBA) using contrast enema. However, there are no ultrasonography (US) microcolon criteria for diagnosing SBA. Therefore,...
BACKGROUND
Microcolon helps diagnose small bowel atresia (SBA) using contrast enema. However, there are no ultrasonography (US) microcolon criteria for diagnosing SBA. Therefore, this study aimed to evaluate colon accuracy and other characteristics for diagnosing SBA by US, using surgical or clinical information as the reference standard.
METHODS
US was performed on 46 neonates aged ≤ 7 days old. In the study group (n = 15), neonates with SBA were confirmed following surgery. In the study group without SBA (n = 15), neonates with other gastrointestinal problems besides SBA were confirmed by surgical or clinical follow-up. Sixteen neonates without gastrointestinal problems were classified as the control group. The colonic diameter was measured, and colonic gas was sought and observed. Statistical analysis was performed to compare US parameters between the study group and other two groups. The optimal cut-off value of the colonic diameter for SBA diagnosis was obtained using receiver operating characteristic analysis.
RESULTS
Colonic diameters (0.5 cm) in the study group (interquartile ranges [IQR], 0.5-0.6 cm) was significantly smaller than that in the group without SBA (0.9 cm; IQR, 0.8-1.2 cm) (P < 0.001) and in the control group (1.2 cm; IQR, 0.8-1.35 cm) (P < 0.001). Optimum cut-off value for diagnosing SBA was 0.65 cm (sensitivity, 90.3%; specificity, 86.7%; accuracy, 89.1%) for the colonic diameter. Combining microcolon and gas-negativity showed the best performance in SBA diagnosis using US, with increased accuracy (91.3%).
CONCLUSION
A colon < 0.65 cm in diameter should be called a microcolon; combining US with gas-negativity is an essential diagnostic basis for SBA.
Topics: Colon; Humans; Infant, Newborn; Intestinal Atresia; Intestinal Obstruction; Intestine, Small
PubMed: 36203132
DOI: 10.1186/s12887-022-03629-z -
Pediatric and Developmental Pathology :... 2022Dominant gamma-smooth muscle actin gene () variants cause clinically diverse forms of visceral myopathy. Many patients undergo intestinal resection or biopsy before... (Review)
Review
BACKGROUND
Dominant gamma-smooth muscle actin gene () variants cause clinically diverse forms of visceral myopathy. Many patients undergo intestinal resection or biopsy before identification of their genetic defect. The pathology of -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) 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 variants is not indicative of an underlying visceral myopathy. Molecular testing should be considered even when no diagnostic intestinal pathology is identified.
Topics: Humans; Actins; Intestinal Pseudo-Obstruction; Urinary Bladder; Myopathies, Structural, Congenital; Colon
PubMed: 35695198
DOI: 10.1177/10935266221107449 -
Urology Nov 2022Fetal interventions are often key to fetal survival and growth; however, they can often have complications causing significant morbidity and mortality. This case...
Fetal interventions are often key to fetal survival and growth; however, they can often have complications causing significant morbidity and mortality. This case highlights not only a complication of fetal surgery, but also a very unusual diagnosis. We present the case of a male fetus who was diagnosed with urethral atresia and subsequently underwent 2 vesicoamniotic shunt placements. At birth, he was diagnosed with Megacystis Microcolon Intestinal Hypoperistalsis Syndrome and was noted to have rectovesical and vesicocutaneous fistulae likely iatrogenically created from shunt placement. While fetal interventions are often required, a multidisciplinary team approach is often necessary as complications occur.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Male; Ultrasonography, Prenatal; Intestinal Pseudo-Obstruction; Fetus; Urinary Bladder; Abnormalities, Multiple; Colon
PubMed: 35623501
DOI: 10.1016/j.urology.2022.05.014 -
FASEB Journal : Official Publication of... Mar 2022The leiomodin1 (LMOD1) gene, encoding a potent actin nucleator, was recently reported as a potential pathogenic gene of megacystis-microcolon-intestinal hypoperistalsis...
The leiomodin1 (LMOD1) gene, encoding a potent actin nucleator, was recently reported as a potential pathogenic gene of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, OMIM 619362). However, only a single patient has been reported to have LMOD1 mutations, and the underlying pathogenic mechanism remains unknown. Here, we described a male infant with LMOD1 mutations presenting typical symptoms of pediatric intestinal pseudo-obstruction (PIPO) but without megacystis and microcolon. Two compound heterozygous missense variants (c.1106C>T, p.T369M; c.1262G>A, p.R421H) were identified, both affecting highly conserved amino acid residues within the second actin-binding site (ABS2) domain of LMOD1. Expression analysis showed that both variants resulted in significantly reduced protein amounts, especially for p.T369M, which was almost undetectable. The reduction was only partially rescued by the proteasome inhibitor MG-132, indicating that there might be proteasome-independent pathways involved in the degradation of the mutant proteins. Molecular modeling showed that variant p.T369M impaired the local protein conformation of the ABS2 domain, while variant p.R421H directly impaired the intermolecular interaction between ABS2 and actin. Accordingly, both variants significantly damaged LMOD1-mediated actin nucleation. These findings provide further human genetic evidence supporting LMOD1 as a pathogenic gene underlying visceral myopathy including PIPO and MMIHS, strengthen the critical role of ABS2 domain in LMOD1-mediated actin nucleation, and moreover, reveal an unrecognized role of ABS2 in protein stability.
Topics: Actins; Autoantigens; Binding Sites; Cytoskeletal Proteins; HeLa Cells; Humans; Infant; Intestinal Pseudo-Obstruction; Loss of Function Mutation; Male; Molecular Docking Simulation; Proteasome Endopeptidase Complex; Protein Binding; Protein Stability
PubMed: 35170814
DOI: 10.1096/fj.202101395R -
Journal of Pediatric Gastroenterology... May 2022The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms...
BACKGROUND AND AIMS
The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease.
METHODS
Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored.
RESULTS
One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores.
CONCLUSIONS
Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.
Topics: Abnormalities, Multiple; Actins; Colon; Female; Humans; Intestinal Pseudo-Obstruction; Male; Phenotype; Pregnancy; Urinary Bladder
PubMed: 35149643
DOI: 10.1097/MPG.0000000000003400 -
Clinics in Colon and Rectal Surgery Jan 2022Despite significant improvements in the management of ulcerative colitis (UC) in parallel with the evolution of therapeutic targets and novel biologics and small... (Review)
Review
Despite significant improvements in the management of ulcerative colitis (UC) in parallel with the evolution of therapeutic targets and novel biologics and small molecules, a subset of medically refractory patients still requires colectomy. Recent population-based studies demonstrate a trend toward a decrease in the rates of surgery for UC patients in the biological era, although the potential of disease modification with these agents is still debated. As the concept of irreversible bowel damage is underexplored in UC, refractory patients can be exposed to multiple treatments losing optimal timing for surgery and further developing complications such as dysplasia/cancer, dysmotility, microcolon, and other functional abnormalities. This review aims to discuss the concept of disease progression in UC, explore the limitations of medical treatment in refractory UC patients, and propose the application of a three-step algorithm that allows timely indication for surgery in clinical practice.
PubMed: 35069028
DOI: 10.1055/s-0041-1740036 -
Journal of Neurogastroenterology and... Jan 2022Chronic intestinal pseudo-obstruction (CIPO) is a clinically heterogeneous syndrome characterized by compromised peristalsis and intestinal obstruction. Variants of...
BACKGROUND/AIMS
Chronic intestinal pseudo-obstruction (CIPO) is a clinically heterogeneous syndrome characterized by compromised peristalsis and intestinal obstruction. Variants of actin gamma 2 (), a protein crucial for correct enteric muscle contraction, have been found in CIPO patients. The aim of this study is to examine the clinical features and variants in Korean patients with CIPO.
METHODS
From January 1995 to August 2020, 12 patients diagnosed with CIPO were included and genetic analysis testing of was performed.
RESULTS
Heterozygous missense variants were found in 6 patients (50.0%). The p.Arg257Cys variant was found in 3 patients, and p.Arg63Gln and p.Arg178His variants were found in 1 patient each. A novel variant, p.Ile193Phe, was found in 1 patient. Three patients were diagnosed at birth, 2 at the age of 1 year, and 1 at 3 years of age. Abnormal prenatal genitourinary ultrasonographic findings were found in all 6 patients; microcolon was found in 4 patients (66.7%), and megacystis in all 6 patients. The pathology showed abnormal ganglion cells as well as myopathic findings. All patients are dependent on total parenteral nutrition and are to date alive.
CONCLUSIONS
variants are commonly found in Korean patients with CIPO. In CIPO patients with megacystis and abnormal prenatal ultrasonography, genetic testing of should be considered. Molecular diagnosis of CIPO is more important than pathologic diagnosis.
PubMed: 34980693
DOI: 10.5056/jnm20243 -
Techniques in Coloproctology Jan 2022
Topics: Colitis; Colon; Fecal Microbiota Transplantation; Humans; Intestinal Obstruction; Male; Young Adult
PubMed: 34751848
DOI: 10.1007/s10151-021-02539-z -
Molecular Genetics & Genomic Medicine Nov 2021Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or...
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus.
BACKGROUND
Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS).
METHODS AND RESULTS
We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non-conserved position of the 5' donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in-frame loss of 71 amino acids and a dominant-negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees.
CONCLUSION
This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype-phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.
Topics: Aortic Dissection; Aortic Aneurysm, Thoracic; Ductus Arteriosus, Patent; Exons; Humans; Male; Mutation; Myosin Heavy Chains; RNA Splice Sites; RNA Splicing; Young Adult
PubMed: 34672437
DOI: 10.1002/mgg3.1814