Visceral Myopathy

A number sign (#) is used with this entry because of evidence that visceral myopathy (VSCM) is caused by heterozygous mutation in the ACTG2 gene (102545) on chromosome 2p13.

Description

Familial visceral myopathy is a rare inherited form of myopathic pseudoobstruction, characterized by impaired function of enteric smooth muscle cells resulting in abnormal intestinal mobility, severe abdominal pain, malnutrition, and even death (Lehtonen et al., 2012). Visceral myopathy represents a phenotypic spectrum of disease characterized by inter- and intrafamilial variability, in which the most severely affected patients exhibit prenatal bladder enlargement, intestinal malrotation, neonatal functional gastrointestinal obstruction, and chronic dependence on total parenteral nutrition (TPN) and urinary catheterization (summary by Wangler et al., 2014).

Another form of visceral myopathy with functional gastrointestinal obstruction is associated with external ophthalmoplegia (277320).

Functional gastrointestinal obstruction also occurs in association with other abnormalities, such as 'prune belly' syndrome (100100) and Barrett esophagus (Mungan syndrome; 611376). Chronic intestinal pseudoobstruction can also be neuropathic in origin (see 609629).

Clinical Features

Weiss (1938) reported megaduodenum alone in 6 persons in 3 generations of a German family.

Tobenkin (1964) described megacystis with nonobstructive vesicoureteral reflux in a mother and her 3 daughters. The history of unilateral nephrectomy in the maternal grandmother suggested that 3 generations may have been affected. No comment on associated megaduodenum was made.

Newton (1968) treated 2 black males who had megaduodenum. One of them also had megacystis and the father probably had megaduodenum. Marfanoid habitus was noted, which raised a question of the mucosal neuroma syndrome (162300). However, microscopic studies showed normal ganglia and presumably no evidence of neuroma. An unusual feature was intermittent bilateral parotid swelling, a feature that Newton (1968) stated had been described in persons with intestinal atony due to Chagas disease (Vieira, 1961). In a discussion included with the paper by Newton (1968), Oberhelman referred to a family with multiple cases of megaduodenum. Familial occurrence was noted in 2 instances by Maldonado et al. (1970).

Berdon et al. (1976) first described what they called the 'megacystis-microcolon-intestinal hypoperistalsis syndrome' (MMIH) in 5 female infants, 2 of whom were sisters. All had marked dilation of the bladder and some had hydronephrosis and the external appearance of 'prune belly' (see 100100). The infants also had microcolon and dilated small intestines. Ganglion cells of the myenteric plexus have usually been normal. Other patients were described, in both sexes (e.g., Krook, 1980), but with a 4:1 female preponderance.

Schuffler and Pope (1977) studied the family of a 15-year-old girl with idiopathic intestinal pseudoobstruction. A 13-year-old brother, the mother, a maternal aunt and one of the aunt's children had mild dysphagia and esophageal motor dysfunction. The mother and the brother had flaccid bladder and bilateral ureteral reflux (193000), respectively. They suggested the designation 'hereditary hollow visceral myopathy.' Smooth muscle degeneration appears to be the basis of the abnormality.

Faulk et al. (1978) described a kindred with at least 18 affected members. Sixteen had symptoms of chronic obstruction of the gastrointestinal and/or urinary tract. Two patients with megaduodenum on contrast studies were asymptomatic. Four had megacolon. Four had megacystis. Specimens from duodenum, jejunum, ileum, colon or urinary bladder in 5 patients showed thinning and extensive collagen replacement of the longitudinal muscle layer. Ganglion cells were normal by light and electron microscopy. Esophageal manometry performed in 3 patients showed decreased gastroesophageal sphincter pressures and absence of contractions in the smooth muscle segment of the esophagus.

Among 27 cases of chronic intestinal pseudoobstruction, Schuffler et al. (1981) found 14 cases of progressive systemic sclerosis, 1 of sclerosing mesenteritis, 1 of jejunal diverticulosis, and 5 with no identifiable cause. Hollow visceral myopathy and visceral neuropathy were present in 4 and 2, respectively. The authors stated that these 2 forms are usually familial and that urologic involvement is sometimes present in the former.

Anuras et al. (1981) reviewed 10 reported families with chronic intestinal pseudoobstruction, 5 of which apparently represented visceral myopathy, with degeneration and fibrosis of the intestine and bladder. In 3, intestinal morphology was normal. Within families, a wide range of severity was observed, with as many as 20% of discovered cases being asymptomatic. In addition, study of families of apparently sporadic cases often uncovered additional affected individuals who had represented a diagnostic enigma to their physicians. By virtue of early diagnosis through such family study, unnecessary laparotomy for presumed mechanical bowel obstruction can be avoided.

Mitros et al. (1982) reported the pathologic findings of familial visceral myopathy in 14 members of 4 families.

Smout et al. (1985) reported a man who presented with achalasia at age 28 years and urinary retention at age 32, and was discovered to have marked dilatation of the entire small intestine at operation for ureteroileocutaneostomy at age 33. The eldest of the patient's 3 daughters had urinary retention and gastrointestinal symptoms. In small intestine specimens from the proband, both smooth muscle and neuronal abnormalities were found; the authors proposed that in this patient the primary defect might be in neuromuscular transmission.

Affected sibs with MMIH were reported by Patel and Carty (1980), Puri et al. (1983), and Oliveira et al. (1983). Winter and Knowles (1986) described affected sisters whose parents were first cousins. A complex heart malformation has been described in some cases (Patel and Carty, 1980; Winter and Knowles, 1986). Couper et al. (1991) discovered multiple cardiac rhabdomyomata in a child with MMIH, who died unexpectedly at 40 months of age.

Ducastelle et al. (1986) described an affected 17-year-old girl whose brother had abnormal esophageal and anorectal manometry and whose father had died of fatal small intestinal occlusion without mechanical obstruction.

Jones et al. (1992) described visceral myopathy in 5 individuals in 4 successive generations with 3 instances of male-to-male transmission. The affected individuals included a 29-year-old physiotherapist whose problems began at age 9 with frequent urinary tract infections, her 28-year-old brother, and her 60-year-old father. Her grandfather had found it necessary to self-administer enemas daily; the great-grandfather survived to age 91, however.

Penman and Lilford (1989) described 2 affected female offspring of a consanguineous Asiatic Indian couple. The first infant was delivered prematurely and died after 7 hours. The second case was diagnosed prenatally by the demonstration of hydronephrosis and distention of the bladder and stomach. Elective abortion was performed.

Anneren et al. (1991) reported what they considered to be the sixth pair of sibs with MMIH. Despite medical and surgical therapy, the patients died at ages 19 days and 2.5 months, respectively.

Guze et al. (1999) described 16 unrelated children, 11 boys and 5 girls, with chronic myopathic intestinal pseudoobstruction, which they designated 'infantile visceral myopathy;' the authors noted that most of their patients would have been diagnosed as having MMIH. In addition to gastrointestinal tract myopathy, all 16 children had bladder or urinary tract involvement, and megacystis was detected prenatally in 7. Four patients had died, 1 of them 7 months after a multiorgan transplant. Three patients had a positive family history, including 1 male who had megacystis at birth and developed constipation, abdominal distention and pain, frequent urination, and failure to thrive. In the second decade of life, he underwent surgery for malrotation, and at age 20 years, he was dependent on parenteral as well as oral nutrition; he also had an enlarged urinary bladder and stomach. Three maternal relatives over 3 generations had symptoms resembling pseudoobstruction, including 2 who died in infancy of 'stomach trouble' and malnutrition, and a maternal cousin who had had constipation, bloating, and problems with urination since childhood. Another patient exhibited vomiting and failure to thrive after birth, requiring parenteral nutrition; at 6 weeks of age, she became constipated, and at 7 months she had massive dilation of the stomach and duodenum, necessitating a return to parenteral nutrition. She also had hypotonic bladder, and antroduodenal manometry confirmed the diagnosis of infantile visceral myopathy at 5 years of age. She underwent bowel transplantation at age 8 years and was doing well almost 2 years later. Her mother suffered from chronic constipation, and family history also included a maternal half brother with enlarged urinary bladder by ultrasound, who died at 4 months of age from sudden infant death syndrome. The third patient presented at birth with vomiting, constipation, abdominal distention, pain, and failure to thrive. At 7 years of age, he had abdominal pain, slow gastric emptying, fecal impaction, flaccid urinary bladder, and he was small for his age. His father, who was diagnosed with visceral myopathy by muscle biopsy and antroduodenal manometry, reported a 5-generation family history of serious digestive problems. Guze et al. (1999) suggested that visceral myopathy represents an autosomal dominant disorder with variable expressivity and incomplete penetrance.

Sipponen et al. (2009) reported a Finnish family in which 7 members over 3 generations had visceral myopathy. Two family members had been previously described (Koskinen et al., 1989). All patients developed intermittent abdominal pain and distention in adolescence due to chronic intestinal pseudoobstruction, which primarily involved the small bowel but also affected the colon in some patients. In addition, 4 patients had endoscopic or histologic evidence of stomach involvement, 1 patient had slight esophageal dilation, and 1 had an inert uterus. None of the affected individuals had signs of megaduodenum, megacystis, or neurologic disease. One family member died at 59 years of age from complications of the disease, including malnutrition, severe electrolyte disturbance, and hypoalbuminemia; another died suddenly at home at 35 years of age, with cause of death reported as pneumonia. Histology of small bowel specimens from 3 patients showed degeneration and fibrosis of the muscularis propria of the intestinal smooth muscle. In addition, the inner circular layer of the muscularis propria contained alpha-smooth muscle actin (102545)-positive inclusion bodies; in more advanced disease, periodic acid-Schiff (PAS)-positive bodies were present as well. No abnormalities of the muscularis mucosae or blood vessels were observed.

Holla et al. (2014) described a 55-year-old Norwegian woman who in early adulthood developed increasing abdominal discomfort, bloating, and diarrhea. Exploratory laparotomy revealed marked dilation and reduced peristalsis of the small bowel but no obstruction; her symptoms continued, and she eventually required TPN due to worsening nutritional status. Her brother, father, and paternal grandfather and great-grandfather had similar symptoms. Histologic examination of full-thickness ileal biopsies from the proband and her affected brother showed haphazardly arranged smooth muscle in the lamina muscularis propria, with lack of separation between the circular and longitudinal layers. Immunohistology revealed a disorderly arrangement of intramyenteric neural tissue with sizable ganglion cell aggregates. In addition, there was swelling of smooth muscle cells with decreased expression of smooth muscle actin.

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.

Diagnosis

Prenatal Diagnosis

In patients with severe manifestations dating from before birth, prenatal diagnosis by ultrasound before 20 weeks should be possible (Vezina et al., 1979). Farrell (1988) described an affected sib pair with intrauterine death of 1 of the sibs. Young et al. (1989) made the diagnosis by ultrasonography in a pregnancy that was monitored due to the previous pregnancy resulting in a male infant who died at 4 hours of age as a consequence of multiple anomalies; these anomalies were believed to include urethral atresia and possibly intestinal atresia. Termination of pregnancy was performed at 18 weeks. Necropsy of the male fetus showed vacuolation and degeneration in smooth muscle of bowel and bladder wall.

Inheritance

Law and Ten Eyck (1962) reported the association of megaduodenum and megacystis in 9 members of a family of Italian extraction. Male-to-male transmission was observed.

Kelly (1977) studied a 4-generation family. Byrne et al. (1977) reported a 3-generation family with many instances of male-to-male transmission. Lewis et al. (1978) observed male-to-male transmission.

Schuffler et al. (1981) suggested autosomal recessive inheritance of a common environmental factor. Two families with dominant inheritance of visceral myopathy were included in their series.

In the review of Anuras et al. (1981) of 10 reported families, 4 families were consistent with dominant inheritance, 3 with X-linked dominant transmission, and 3 with recessive inheritance. Several instances of father-to-son transmission are on record.

Guze et al. (1999) studied 16 probands, 11 male and 5 female, with infantile visceral myopathy, from ethnically and geographically diverse families within the United States. There were no consanguineous matings and no similarly affected sibs, and only 3 probands had a family history suggestive of affected relatives. Guze et al. (1999) suspected that new dominant mutations were responsible for some cases, whereas in others a dominant gene with variable expressivity and incomplete penetrance might be responsible.

Cytogenetics

Chamyan et al. (2001) reported megacystis-microcolon-intestinal hypoperistalsis syndrome in a fetus with trisomy 18. No ganglion cells were present in the colon or bladder.

Molecular Genetics

In a 3-generation Finnish family with visceral myopathy, originally reported by Sipponen et al. (2009), Lehtonen et al. (2012) performed exome sequencing and identified a missense mutation in the ACTG2 gene (R148S; 102545.0001). The mutation, which segregated with disease, was not found in 280 Finnish controls.

In a 55-year-old Norwegian woman with chronic intestinal pseudoobstruction due to biopsy-proven visceral myopathy, Holla et al. (2014) performed next-generation sequencing and identified heterozygosity for the ACTG2 R148S mutation, which was not found in her unaffected mother.

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 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., 102545.0003-102545.0009), of which 10 carried apparent de novo mutations. Noting the phenotypic variability of mutation-positive patients, Wangler et al. (2014) suggested that these clinical entities represent a spectrum of ACTG2-related disorders.

Exclusion Studies

Because of observations in mice homozygous for disruption of the alpha-3/beta-4 neuronal nicotinic acetylcholine receptor genes (CHRNA3, 118503; CHRNB4, 118509), Lev-Lehman et al. (2001) screened for mutations in these genes, both of which map to human chromosome 15q24, in patients with MMIH. They found no loss-of-function mutations in either gene but found high frequency polymorphisms in both.

Animal Model

Xu et al. (1999, 1999) produced the MMIH phenotype in Chrna3/Chrnb4 knockout mice and postulated that the basic defect in the human disorder might reside in 1 of these genes.