Megacystis-microcolon-intestinal hypoperistalsis syndrome: don't forget the bladder.

PURPOSE: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a well described clinical condition, but reports are focused on microcolon and intestinal hypoperistalsis, while data on bladder management are scant. Aim of the study is to present urological concerns in MMIHS. METHODS: Retrospective evaluation of clinical data on urological management of MMIHS patients treated in the last 10 years. RESULTS: Six patients were enrolled (3 male, 3 female). Three girls had prenatal diagnosis of megacystis (1 vesicoamniotic shunt was placed). All patients had genetic diagnosis: 5 had ACTG2 gene mutations and 1 MYH11 mutation. All patients were addressed to our attention for urinary symptoms, such as urinary retention, urinary tract infections, acute renal injury. Two patients presented frequent stoma prolapses. All children underwent a complete urological evaluation, and then started a bladder management protocol (clean intermittent catheterization, via urethra or cystostomy-tube placement), with improvement of urinary infections, upper urinary tract dilation and stoma prolapses, if present. All patients had good renal function at last follow-up. CONCLUSION: We believe that MMIHS patients must be addressed soon and before onset of symptoms for a multidisciplinary evaluation, including an early assessment by a pediatric urologist expert in functional disorder, to preserve renal function at its best.

A lmod1a mutation causes megacystis microcolon intestinal hypoperistalsis in a CRISPR/Cas9-modified zebrafish model.

PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. METHODS: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. RESULTS: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. CONCLUSION: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.

Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton.

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.

Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction.

Variants in the ACTG2 gene, encoding a protein crucial for correct enteric muscle contraction, have been found in patients affected with chronic intestinal pseudo-obstruction, either congenital or late-onset visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Here we report about ten pediatric and one adult patients, from nine families, carrying ACTG2 variants: four show novel still unpublished missense variants, including one that is apparently transmitted according to a recessive mode of inheritance. Four of the remaining five probands carry variants affecting arginine residues, that have already been associated with a severe phenotype. A de novo occurrence of the variants could be confirmed in six of these families. Since a genotype-phenotype correlation is affected by extrinsic factors, such as, diagnosis delay, quality of clinical management, and intra-familial variability, we have undertaken 3D molecular modeling to get further insights into the effects of the variants here described. The present findings and further ACTG2 testing of patients presenting with intestinal pseudo-obstruction, will improve our understanding of visceral myopathies, including implications in the prognosis and genetic counseling of this set of severe disorders.

Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs∗51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.

Fetal megacystis-microcolon: Genetic mutational spectrum and identification of PDCL3 as a novel candidate gene.

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.

16p13.11 microdeletion uncovers loss-of-function of a MYH11 missense variant in a patient with megacystis-microcolon-intestinal-hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a rare condition that affects smooth muscle cells, is caused by biallelic null alleles in MYH11. We report on a girl with MMIHS in addition to growth hormone deficiency, central hypothyroidism and a tonically dilated pupil with accommodation deficit. Sanger sequencing and arrayCGH uncovered the novel heterozygous missense variant c.379C>T in MYH11 and a heterozygous 1.3 Mb deletion in 16q13.11 encompassing MYH11, respectively. Her mother carries the deletion, whereas her father is heterozygous for the c.379C>T p.(Pro127Ser) change. Proline 127 is crucial for the formation of the Adenosine triphosphate binding pocket of the MYH11 motor domain and molecular modeling indicated that p.Pro127Ser alters nucleotide binding properties. Thus, the unusual and complex clinical presentation of the patient results from compound heterozygosity for a 16p13.11 microdeletion including the entire MYH11 gene and a loss-of-function missense variant on the remaining MYH11 allele. In conclusion, we recommend genetic testing both for MYH11 sequence alterations and copy number imbalances in individuals with MMIHS and smooth muscle cell-associated abnormalities in additional organs, that is, multisystemic smooth muscle dysfunction.

Exploring the complexities of megacystis-microcolon-intestinal hypoperistalsis syndrome: insights from genetic studies.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy. Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals.

Syndromic and single gene disorders associated with fetal megacystis (I): Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS).

Fetal megacystis has been reported to be associated with chromosomal abnormalities, megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), obstructive uropathy, prune belly syndrome, cloacal anomalies, limb-body wall complex, amniotic band syndrome, anorectal malformations, VACTERL association (vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies and limb abnormalities) and fetal overgrowth syndrome such as Bechwith-Wiedemann syndrome and Sotos syndrome. This review provides an overview of syndromic and single gene disorders associated with fetal megacystis which is useful for genetic counseling at prenatal diagnosis of fetal megacystis.

Compound heterozygous loss of function variants in MYL9 in a child with megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), or "visceral myopathy," is a severe early onset disorder characterized by impaired muscle contractility in the bladder and intestines. Five genes are linked to MMIHS: primarily ACTG2, but also LMOD1, MYH11, MYLK, and MYL9. Here we describe a three-year-old girl with bilateral hydronephrosis diagnosed at 20 weeks gestation and congenital mydriasis (both of which have been previously observed among individuals with MMIHS). A clinical diagnosis of MMIHS was made based upon the presence of megacystis, lack of urinary bladder peristalsis, and intestinal pseudo-obstruction. After initial testing of ACTG2 was negative, further sequencing and deletion/duplication testing was performed on the LMOD1, MYH11,MYLK, and MYL9 genes. We identified two heterozygous loss of function variants in MYL9: an exon 4 deletion and a nine base pair deletion that removes the canonical splicing donor site at exon 2 (NM_006097.5:c.184+2_184+10del). Parental testing confirmed these variants to be in trans in our proband. To our knowledge, only one other individual with MMIHS has biallelic mutations in MYL9 (a homozygous deletion encompassing exon 4). We suggest MYL9 be targeted on genetic testing panels for MMIHS, smooth muscle myopathies, and cardiovascular phenotypes.

Megacystis microcolon intestinal hypoperistalsis syndrome: Case series and updated review of the literature with an emphasis on urologic management.

INTRODUCTION: Megacystis microcolon intestinal hypoperistalsis (MMIHS) is a rare disorder characterized by distended nonobstructed bladder, microcolon, and decreased intestinal peristalsis. MMIHS has a particularly poor prognosis; however, when appropriately managed, survival can be prolonged. STUDY DESIGN: A systematic review (1996-2016) was performed with the key words "megacystis microcolon intestinal hypoperistalsis syndrome." In addition, a case series of four patients is presented as well as algorithms for the diagnosis and treatment of MMIHS. RESULTS: 135 patients with MMIHS were identified in the literature. 73% (88/121) of the patients were female, 65% underwent diagnostic biopsy (64/99), and 63% (66/106) were identified with prenatal imaging. The majority of patients were treated with TPN as well as gastrostomy or ileostomy and CIC, however 15% (18/116) received multivisceral or intestinal transplant, and 30% (22/73) had a vesicostomy. The survival rate was 57% (68/121). CONCLUSION: Appropriate management of MMIHS patients is crucial. An enlarged, acontractile bladder in a child with bowel motility problems should be considered diagnostic. Bladder distension can be managed with CIC or vesicostomy in addition to prophylactic antibiotics if frequent urinary tract infections are present. These patients often require gastrostomy or ileostomy as well as total parenteral nutrition. This management has led to significant improvement in survival rates.

Megacystis microcolon intestinal hypoperistalsis syndrome: A report of a nationwide survey in Japan.

BACKGROUND: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare condition with a poor outcome. A nationwide survey was conducted to identify the clinical features and outcomes of MMIHS in Japan. METHODS: Data were collected via a questionnaire, which was sent to 353 pediatric/pediatric surgical departments in Japan. RESULTS: Of the 28 patients registered as having a certain diagnosis of MMIHS, 19 (male/female, 3/16) patients were analyzed. All of the patients developed functional bowel obstruction in the neonatal period and showed a distended bladder and microcolon in the radiological examination. A histopathology assessment of the full-thickness of intestinal specimens showed no pathological abnormalities in all patients. Although various medications were given, the patients did not show significant improvement. Drainage stomas were created in the jejunum (n=11) and colon (n=5). Sixteen patients were maintained by parenteral nutrition (PN). Nine patients died of sepsis or liver failure. The five- and ten-year survival rates were 63% and 57%, respectively. CONCLUSIONS: MMIHS patients developed severe functional intestinal obstruction in the neonatal period and had no specific therapeutic intervention. The majority of MMIHS patients required long-term PN. Small bowel or multivisceral transplantation may be necessary to improve the outcome of this condition.

Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome.

We report a case of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) in a newborn female infant who presented with an abdominal mass, absent bowel sounds, and feeding intolerance with bilious emesis. MMIHS is a rare congenital bowel and bladder defect requiring surgery and chronic total parenteral nutrition in an attempt to sustain life. With few exceptions, it is predominately fatal within the first six months of life. We describe the relevant clinical and radiologic findings with ultrasound correlation of this case followed by a brief review of literature included in the discussion.