ORPHA: 2241;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.1 | Megacystis-microcolon-intestinal hypoperistalsis syndrome 5 | 619431 | Autosomal dominant | 3 | ACTG2 | 102545 |
A number sign (#) is used with this entry because of evidence that megacystis-microcolon-intestinal hypoperistalsis syndrome-5 (MMIHS5) is caused by heterozygous mutation in the ACTG2 gene (102545) on chromosome 2p13.
Visceral myopathy-1 (VSCM1; 155310), which overlaps phenotypically with MMIHS5, is also caused by heterozygous mutation in the ACTG2 gene.
Megacystis-microcolon-intestinal hypoperistalsis syndrome-5 (MMIHS5) is a form of visceral myopathy characterized by significant inter- and intrafamilial variability, with the most severely affected patients exhibiting prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization (Wangler et al., 2014).
For a general phenotypic description and discussion of genetic heterogeneity of MMIHS, see MMIHS1 (249210).
Thorson et al. (2014) studied 2 children with megacystis and intestinal pseudoobstruction. The first was a girl born with megacystis and hydronephrosis as well as malrotation and pseudoobstruction of the intestine. She was dependent on TPN and developed end-stage liver disease with portal hypertension. Full-thickness biopsy of the large intestine confirmed the presence of ganglion cells; biopsy of the jejunum showed a thin outer muscular layer. At 8 months of age, she underwent en bloc transplant of stomach, liver, pancreas, and small intestine; at age 12 years, she was doing well but required intermittent urinary catheterization. The second patient was a male infant who was diagnosed at 19 weeks' gestation with megacystis, bilateral hydroureters, and anhydramnios. Postnatal evaluation revealed intestinal malrotation, microcolon, and dilated proximal small intestine.
Halim et al. (2016) reported 8 sporadic patients with 'typical' MMIHS and mutations in the ACTG2 gene. Of the 5 patients for whom information was available, prenatal findings included megacystis, hydroureter, hydronephrosis, and polyhydramnios. All patients had enlarged bladder and microcolon; 6 who were evaluated had documented hypoperistalsis; and 5 had malrotation of the intestines. Only 1 patient (S6) was alive at age 24 years, on parenteral and enteral nutrition; another (S1) died at age 23 years from multiple organ failure, as did patient S5 at age 8 months. Two others (S3 and S4) died at age 5 days and 5 months, respectively, upon discontinuation of treatment.
Moreno et al. (2016) reported 3 unrelated Brazilian children with MMIHS and mutations in ACTG2. A male infant (patient 3) and a female infant (patient 4) died despite supportive therapy, at 7 months and 11 months of age, respectively. Patient 5 was alive at 5 months of age, maintained on total parenteral nutrition. Histology of the stomach and small and large intestine in patient 4 was reported as normal, whereas histology in patient 5 showed enterocolitis.
Milunsky et al. (2017) reported 7 patients from 4 families with severe chronic intestinal pseudoobstruction (CIPO) and megacystis who had mutations in ACTG2. Megacystis was present prenatally and evident at birth in all 7 patients. Three patients died, at 6 months, 2 years, and 11.5 years of age. Four patients required long-term TPN, 1 of whom underwent multiorgan transplantation at age 38, after 35 years on TPN. Three each had gastrostomy, ileostomy, and colectomy, and 6 required lifelong bladder catheterization due to megacystis. None had microcolon.
The transmission pattern of MMIHS5 in families reported by Wangler et al. (2014) and Halim et al. (2016) was consistent with autosomal dominant inheritance. The heterozygous mutations in many families occurred de novo.
In a 12-year-old girl and an unrelated male infant with megacystis and intestinal pseudoobstruction, Thorson et al. (2014) identified heterozygosity for de novo missense mutations in the ACTG2 gene, R178L (102545.0002) and R178C (102545.0003), respectively. Noting that the less severe phenotype of visceral myopathy (VSCM1; 155310) is also caused by mutation in the ACTG2 gene, Thorson et al. (2014) suggested that MMIH and visceral myopathy represent the spectrum of a single disease, with intestinal hypoperistalsis as the common denominator.
Wangler et al. (2014) studied a cohort of 27 probands who had been diagnosed with MMIH and related phenotypes, including intestinal pseudoobstruction, hollow visceral myopathy, and 'prune belly' syndrome (see 100100). Whole-exome sequencing followed by targeted Sanger sequencing identified heterozygous missense variants in the ACTG2 gene in 15 unrelated patients (see, e.g., 102545.0003, 102545.0004, 102545.0006, 102545.0007, and 102545.0009), of which 10 carried apparent de novo mutations. Noting the phenotypic variability of mutation-positive patients, the authors suggested that ACTG2 is responsible for a spectrum of smooth muscle disease.
Halim et al. (2016) screened the ACTG2 gene in a cohort of 11 patients with typical features of MMIHS and identified heterozygous missense mutations in 8 patients with sporadic disease (102545.0002-102545.0004, 102545.0006, and 102545.0010). The mutations were shown to have arisen de novo in the 3 probands for whom familial DNA was available. No mutations were identified in the 3 remaining patients from 2 consanguineous families.
By Sanger sequencing of the ACTG2 gene in a cohort of 7 Brazilian children with 'visceral myopathy phenotypes,' Moreno et al. (2016) identified 3 unrelated patients (patients 3, 4, and 5) with MMIHS who were heterozygous for missense mutations in ACTG2 (102545.0002, 102545.0003, and 102545.0013). The mutations arose de novo in each proband, as they were not found in the respective parents. The authors also identified a 5-year-old Brazilian girl with chronic intestinal pseudoobstruction and a heterozygous missense mutation in the ACTG2 gene (T195I; 102545.0011)
By whole-exome and Sanger sequencing in a cohort of 28 probands who had CIPO with or without megacystis, Milunsky et al. (2017) identified 4 probands with MMIHS and heterozygous mutations in the ACTG2 gene: 3 probands, including 1 with an affected family member (family A), had the R257C mutation (102545.0007), and 1 proband and 2 affected family members (family B) carried the R40H mutation (102545.0005).
Assia Batzir et al. (2020) studied a cohort of 53 families with MMIHS, including the 15 ACTG2 mutation-positive families previously reported by Wangler et al. (2014). Mutations in the ACTG2 gene were present in 33 (62%) of the families (see, e.g., 102545.0002, 102545.0003, 102545.0005-102545.0008, and 102545.0010). The majority of individuals who tested positive for ACTG2 variants exhibited the classic MMIHS phenotype, including a combination of symptoms suggesting bladder and intestinal dysmotility. The authors noted that ACTG2-positive patients were more likely to have more severe disease than ACTG2-negative patients. Within the ACTG2-positive group, poor outcomes, including TPN dependence, multiorgan transplantation, or death, were invariably associated with arginine missense alleles. Analysis of specific residues suggested a spectrum of severity, in which R178 involvement causes the most severe disease, with R257 next in severity, followed by R40.
Assia Batzir, N. A., Kishor Bhagwat, P. K., Larson, A., Akdemir, Z. C., Bagtaj, M., Bofferding, L., Bosanko, K. B., Bouassida, S., Callewaert, B., Cannon, A., Colon, Y. E., Garnica, A. D., and 25 others. Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum. Mutat. 41: 641-654, 2020. [PubMed: 31769566] [Full Text: https://doi.org/10.1002/humu.23960]
Halim, D., Hofstra, R. M. W., Signorile, L., Verdijk, R. M., van der Werf, C. S., Sribudiani, Y., Brouwer, R. W. W., van Ijcken, W. F. J., Dahl, N., Verheij, J. B. G. M., Baumann, C., Kerner, J., van Bever, Y., Galjart, N., Wijnen, R. M. H., Tibboel, D., Burns, A. J., Muller, F., Brooks, A. S., Alves, M. M. ACTG2 variants impair actin polymerization in sporadic megacystis microcolon intestinal hypoperistalsis syndrome. Hum. Molec. Genet. 25: 571-583, 2016. [PubMed: 26647307] [Full Text: https://doi.org/10.1093/hmg/ddv497]
Milunsky, A., Baldwin, C., Zhang, X., Primack, D., Curnow, A., Milunsky, J. Diagnosis of chronic intestinal pseudo-obstruction and megacystis by sequencing the ACTG2 gene. J. Pediat. Gastroent. Nutr. 65: 384-387, 2017. [PubMed: 28422808] [Full Text: https://doi.org/10.1097/MPG.0000000000001608]
Moreno, C. A., Metze, K., Lomazi, E. A., Bertola, D. R., Barbosa, R. H. A., Cosentino, V., Sobreira, N., Cavalcanti, D. P. Visceral myopathy: clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am. J. Med. Genet. 170A: 2965-2974, 2016. [PubMed: 27481187] [Full Text: https://doi.org/10.1002/ajmg.a.37857]
Thorson, W., Diaz-Horta, O., Foster, J., II., Spiliopoulos, M., Quintero, R., Farooq, A., Blanton, S., Tekin, M. De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis. Hum. Genet. 133: 737-742, 2014. [PubMed: 24337657] [Full Text: https://doi.org/10.1007/s00439-013-1406-0]
Wangler, M. F., Gonzaga-Jauregui, C., Gambin, T., Penney, S., Moss, T., Chopra, A., Probst, F. J., Xia, F., Yang, Y., Werlin, S., Eglite, I., Kornejeva, L., and 12 others. Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome. PLoS Genet. 10: e1004258, 2014. Note: Electronic Article. [PubMed: 24676022] [Full Text: https://doi.org/10.1371/journal.pgen.1004258]