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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

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ACTG2-Related Disorders

, MD
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas
, MD
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Initial Posting: .

Summary

Clinical characeristics.

ACTG2-related disorders are a subset of visceral myopathy with variable involvement of the bladder and intestine. Bladder involvement can range from neonatal megacystis and megaureter (with its most extreme form of prune belly syndrome) at the more severe end, to recurrent urinary tract infections and bladder dysfunction at the milder end. Chronic bladder dysfunction carries a high risk for urinary tract infections, dilation of the upper urinary tract, and impaired renal function. Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, megacystic microcolon intestinal hypoperistalsis syndrome (MMIHS), and chronic intestinal pseudoobstruction (CIPO) in neonates, children, and adults. Affected infants (with or without evidence of intestinal malrotation) often present with feeding intolerance and findings of non-mechanical bowel obstruction that persist after successful surgical correction of malrotation. Individuals who develop manifestations of CIPO in later childhood or adulthood often experience episodic waxing and waning of bowel motility. They may undergo frequent abdominal surgeries (perhaps related to malrotation or adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel, often becoming dependent on total parenteral nutrition (TPN).

Diagnosis/testing.

The diagnosis of an ACTG2-related disorder is established in a proband by the presence of a heterozygous pathogenic variant in ACTG2.

Management.

Treatment of manifestations: Management requires a multidisciplinary approach that includes primary care providers, gastroenterologists, general surgeons, urologists, nephrologists, dieticians, and social workers. Chronic bladder dysfunction typically requires management by a urologist and can involve routine urinary catheterization or diversion to reduce the risk of dilation of the upper urinary tract and associated risk for urinary tract infection and renal functional impairment. CIPO typically requires management by a gastroenterologist and nutritionist familiar with intestinal motility disorders.

Prevention of secondary complications: Clean and safe practices in the use of indwelling intravenous catheters for administration of TPN and bladder catheterization can help prevent infections. Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period.

Surveillance: Should be individualized taking into account:

  • The association between urinary tract infections and chronic bladder dysfunction and the increased risk for dilation of the upper urinary tract, and renal functional impairment
  • Need for routine evaluation of liver function in those dependent on long-term TPN.

Agents/circumstances to avoid: For those with CIPO, high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk as early diagnosis may help prevent unnecessary surgery for symptoms of intestinal obstruction and may allow early evaluation of bladder function, the urinary tract (for evidence of dilation), and renal function.

Pregnancy management: When a fetus at risk for an ACTG2-related disorder has evidence of bladder distention on prenatal ultrasound examination, consultation with a maternal fetal medicine specialist is recommended.

Genetic counseling.

ACTG2-related disorders are inherited in an autosomal dominant manner. While the exact proportion of inherited vs de novo pathogenic variants is unknown, current data suggest that de novo pathogenic variants are common. Each child of an individual with an ACTG2-related disorder has a 50% chance of inheriting the pathogenic variant. Although penetrance of ACTG2-related disorders appears to be complete, the severity of clinical findings can vary within a family. Prenatal testing for pregnancies at increased risk is possible if the ACTG2 pathogenic variant has been identified in an affected family member.

GeneReview Scope

ACTG2-Related Disorders: Included Phenotypes 1
  • Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)
  • Prune belly sequence
  • Chronic intestinal pseudoobstruction (CIPO)

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

ACTG2-related disorders are a subset of visceral myopathy with variable involvement of the bladder and intestine.

Suggestive Findings

ACTG2-related disorders should be suspected in individuals with bladder and/or intestinal involvement that can range in a continuum from severe in neonates to more mild in older children and adults.

Bladder involvement can range from neonatal megacystis and megaureter (with its most extreme form of prune belly syndrome) at the more severe end to recurrent urinary tract infections and bladder dysfunction at the milder end. Chronic bladder dysfunction has a high risk of urinary tract infections, dilation of the upper urinary tract, and impaired renal function.

Suggestive bladder findings:

  • Prenatal ultrasound revealing megacystis, defined according to trimester [Fievet et al 2014]:
    • First trimester: bladder diameter >6 mm
    • Second and third trimesters: enlarged bladder with failure to empty within 45 minutes
  • In neonates: prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility
  • Postnatal ultrasound examination or cystogram revealing an enlarged bladder
  • In individuals of any age: unexplained chronic functional bladder impairment of voiding without mechanical blockage

Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, and megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) to chronic intestinal pseudoobstruction (CIPO) in neonates, infants, children, and adults.

Suggestive intestinal findings:

  • Neonatal bilious emesis, abdominal distention, and feeding intolerance
  • Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation
  • Neonatal microcolon
  • In individuals of any age: chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage).

Suggested specific diagnostic findings [Gabbard & Lacy 2013]:

  • Symptoms lasting >6 months, or >2 months from birth
  • Evidence of delayed GI transit and/or decreased GI motility
  • Imaging studies that do not show mechanical obstruction
  • Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [Rudolph et al 1997]

Establishing the Diagnosis

The diagnosis of an ACTG2-related disorder is established in a proband by the presence of a heterozygous pathogenic variant in ACTG2 (see Table 1).

Between 50% and 70% of individuals with a clinical diagnosis of MMIHS and a significant but unknown fraction of individuals with a diagnosis of CIPO have a heterozygous pathogenic ACTG2 missense variant.

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of ACTG2 is performed first. Deletion/duplication analysis may be considered if no pathogenic variant is found; however, all pathogenic variants identified to date are missense variants, and no exon or whole-gene deletions/duplications have been identified as a cause of ACTG2-related disorders.
  • A multi-gene panel that includes ACTG2 and other genes of interest (see Differential Diagnosis) may also be used. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Summary of Molecular Genetic Testing Used in ACTG2-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ACTG2Sequence analysis 223/23 3, 4
Gene-targeted deletion/duplication analysis 5None detected to date
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

2/2 probands in Thorson et al [2014], 15/15 probands with ACTG2-related disorders in Wangler et al [2014], 3/3 probands in Tuzovic et al [2015], the case/family reports of Lehtonen et al [2012], Holla et al [2014], and Klar et al [2015]

4.

All pathogenic variants identified to date are missense.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Examples of methods that may be used include: quantitative PCR, long-range PCR, and multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

A number of clinical phenotypes characterized by smooth muscle dysfunction affecting bowel and bladder (including diagnoses such as megacystis-microcolon-intestinal hypoperistalsis syndrome [MMIHS] and chronic intestinal pseudoobstruction [CIPO]) have been described and reported in detail [Puri & Shinkai 2005]. At this time it is not known what percentage of the phenotypes reported before 2012 were caused by mutation of ACTG2 versus other causes.

Molecularly Confirmed ACTG2-Related Disorders

Because ACTG2 pathogenic variants have only recently been identified as a cause of MMIHS, CIPO, and similar phenotypes, the number of affected individuals reported to date is small [Lehtonen et al 2012, Holla et al 2014, Thorson et al 2014, Wangler et al 2014]. (See Table 2.) Thus, current understanding of the breadth of the phenotype and natural history of ACTG2-related disorders is limited, but expected to evolve over time.

Individuals with an ACTG2-related disorder experience functional defects of smooth muscle involving both bladder and bowel. General clinical patterns include neonates with a de novo ACTG2 pathogenic variant who experience severe functional impairment of bowel and bladder consistent with MMIHS, and individuals with an inherited (familial) ACTG2 pathogenic variant who experience later-onset CIPO. Individuals with ACTG2-related disorders usually have normal intellect.

Table 2.

Summary of Bladder and Intestinal Findings in Individuals with Molecularly Confirmed ACTG2-Related Disorders

FindingStudy
Sipponen et al [2009], Lehtonen et al [2012]Thorson et al [2014]Holla et al [2014]Wangler et al [2014]Klar et al [2015]
BladderPrenatal or postnatal megacystisNot reported2Not Reported87
Prune belly syndromeNot reported0Not Reported10
Chronic functional impairment22Not Reported87
IntestinalMicrocolonNot reported1Not Reported50
Bilious emesis or inability to tolerate feeds as a neonateNot reported2Not Reported70
History of abdominal surgery321127
Dependent on parenteral nutrition2 (intermittent)2070
CIPO70187
De novo cases (# of families)0 (0)2 (2)0 (0)10 (10)0 (0)
Dominant familial cases (# of families)8 (1)0 (0)1 (1)9 (3)7 (1)
Undetermined inheritance cases (# of families)0 (0)0 (0)0 (0)2 (2)0 (0)
Total molecularly confirmed cases (total # of families)8 (1)2 (2)1 (1)21 (15)7 (1)

Urologic. From a recent series the majority of individuals with a de novo ACTG2 pathogenic variant had prenatal or postnatal megacystis and approximately one third had had a vesicoamniotic shunt placed prenatally [Wangler et al 2014].

Prune belly syndrome, characterized by lack of abdominal wall musculature, cryptorchidism in males, and distention of the urinary tract, was reported in one male with MMIHS and a de novo ACTG2 pathogenic variant [Wangler et al 2014].

Chronic bladder functional impairment seen in the majority of individuals with an ACTG2 de novo pathogenic variant can require lifelong bladder catheterization.

Gastrointestinal. The majority of neonates with a de novo ACTG2 pathogenic variant are unable to tolerate feedings. Likewise, intestinal malrotation is common and while many undergo a Ladd surgical procedure, many experience persistent symptoms of bowel obstruction after surgical recovery [Wangler et al 2014].

Affected individuals can experience episodic improvement of bowel motility, loss of bowel motility over time, or waxing and waning of reduced bowel motility. Affected individuals may undergo frequent abdominal surgeries (perhaps related to malrotation or presumed adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel.

In many families with a dominantly inherited ACTG2 pathogenic variant and waxing and waning CIPO, affected individuals report lifelong gastrointestinal discomfort and symptoms with episodes resulting in surgery and hospitalization. These individuals can survive to an advanced age.

Long-term survival. Long-term survival in those with a de novo ACTG2 pathogenic variant usually requires total parenteral nutrition and urinary catheterization or diversion. Most long-term survivors have ileostomies.

Large series of individuals with MMIHS reported before the molecular basis of ACTG2-related disorders was known suggested that long-term survival was uncommon because the majority die in childhood or infancy of sepsis, organ failure, and/or malnutrition [Gosemann & Puri 2011]. In contrast, in families with an inherited ACTG2 pathogenic variant, some family members with the pathogenic variant have MMIHS and others with the same variant have milder phenotypes, living into adolescence and early adulthood [Wangler et al 2014].

It is not clear whether differences in prognosis for individuals with an ACTG2-related disorder compared to those with MMIHS of unknown cause reflect advances in medical management of parenteral nutrition or other factors.

Smooth Muscle Dysfunction (including MMIHS and CIPO) of Unknown Cause

Several studies have explored the clinical features of individuals with MMIHS and CIPO, but the proportion due to an ACTG2 pathogenic variant versus other causes is not known. Therefore, these studies may encompass patient populations that combine ACTG2-related disorders and those of other etiologies.

Urologic. Prenatal ultrasound examination is reported to identify megacystis in 88% and gastrointestinal abnormalities in 24% [Tuzovic et al 2014].

Radiographic studies after delivery could reveal megacystis, hydronephrosis, vesicoureteral reflux, and/or the presence of microcolon [Ballisty et al 2013].

Although urinary obstruction and its potential adverse effect on renal function are often a concern in individuals with MMIHS, the long-term consequences for kidney function are not known. In one report of 709 individuals with fetal dilation of the urinary tract of diverse causes (e.g., posterior urethral valves and other types of mechanical obstruction not consistent with MMIHS), 17 instances of MMIHS were identified among 98 individuals with megacystis [Al-Hazmi et al 2012]. In this series, almost 30% (86/289) of those with severe fetal urinary tract dilatation had an abnormal serum creatinine concentration at age two years.

Gastrointestinal. Chronic intestinal pseudoobstruction (CIPO) has been reported at ages ranging from infancy to adulthood. After onset, progression to severe digestive dysfunction can range from one to 46 years [De Giorgio et al 2011].

Some individuals with CIPO may undergo exploratory laparotomy without identification of an obstructive lesion.

Pathology. Numerous histopathologic studies on infants with MMIHS have had variable or inconsistent results [Puri & Shinkai 2005]. Findings have included alterations in ganglion cells (rare), vacuolar degeneration in the smooth muscle layer with connective tissue infiltration between muscle cells in bowel and bladder, excess muscle glycogen, and absent or reduced smooth muscle actin [Puri & Shinkai 2005].

Visceral myopathy reveals the presence of vacuoles or fibrous replacement in the smooth muscle layer (muscularis propria) in a full-thickness intestinal biopsy [Huang et al 2013b].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

To date all reported ACTG2 pathogenic variants have been missense variants, many of which affect arginine residues of the γ-2 actin protein. The same missense variants have been seen across the phenotypic spectrum from neonatal MMIHS to later-onset chronic intestinal pseudoobstruction. Of note, disease caused by a de novo pathogenic variant is often more severe than inherited disease.

Heterozygous null variants may be benign; however, this is not known with certainty.

Penetrance

Thus far, penetrance of ACTG2-related disorders appears to be complete, as no family members heterozygous for a known ACTG2 pathogenic variant have been noted to be completely symptom free. However, the clinical severity can range within a family, and mildly affected individuals may not be aware of the diagnosis. Examples: (1) one individual (in a multi-generation Finnish family) with an ACTG2 pathogenic variant reported episodic mild abdominal pain but no surgery and no signs of visceral myopathy at age 19 years [Lehtonen et al 2012]; (2) one individual diagnosed with “spastic colon” and irritable bowel syndrome had not required surgery or intervention in middle age [Wangler et al 2014].

Nomenclature

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) may also be referred to as familial visceral myopathy or Berdon syndrome.

The broad term “hollow visceral myopathy” includes phenotypically related disorders caused by pathogenic variants in other genes (e.g., ACTA2), and, therefore, should not be used as a synonym for ACTG2-related disorders [Milewicz et al 2010].

Prune belly sequence may also be referred to as Eagle-Barrett syndrome.

Prevalence

To date 47 individuals (from 23 families) have been reported to have a molecularly confirmed ACTG2-related disorder [Lehtonen et al 2012, Holla et al 2014, Thorson et al 2014, Wangler et al 2014]. (See Table 2.)

A total of 227 individuals with MMIHS were reported between 1976 and 2011 [Gosemann & Puri 2011]. The proportion with an ACTG2-related disorder is unknown.

It is estimated that 100 individuals per year in the United States are diagnosed with CIPO [De Giorgio et al 2011]. The proportion with an ACTG2-related disorder is unknown.

Differential Diagnosis

Since many individuals with visceral myopathy with variable involvement of the bladder and intestine do not have an ACTG2 pathogenic variant, mutation of other genes must contribute to the etiology of this phenotype (Table 3). Because mydriasis has been noted in some individuals with MMIHS (megacystis-microcolon-intestinal hypoperistalsis syndrome) [McClelland et al 2013] but not in those with an ACTG2-related disorder, the presence of mydriasis may suggest a differ disorder.

Table 3.

Inherited Disorders in the Differential Diagnosis for ACTG2-Related Disorders

GeneInheritanceSevere GI or GU Involvement or BothDistinguishing Clinical Features
MYH11ARBothPatent ductus arteriosus in one individual
ACTA2ADBothVascular aneurysms and dissections, patent ductus arteriosus, mydriasis
FLNAXLGIPeriventricular heterotopia in males, seizures in females
TYMPARGIMNGIE: ptosis, ophthalmoplegia and ophthalmoparesis, hearing loss, neuropathy
EDNRB, EDN3, or SOX10AD or ARGIWaardenburg syndrome with pigmentary abnormalities
SGOL1ARGICAID: sick sinus syndrome, atrial dysrhythmias
RAD21ARGIMungan syndrome: Barrett esophagus, megaduodenum, cardiac abnormalities
CHRM3ARGUPosterior urethral valves and prune belly syndrome
CHRNA3, CHRNB2, CHRNB4NAGUMouse models with mydriasis and megacystis

GI = gastrointestinal

GU = genitourinary

NA = not applicable

MNGIE = mitochondrial neurogastrointestinal encephalopathy

CAID = chronic atrial and intestinal dysrhythmia

MYH11. Mutation of this gene was identified in a child with MMIHS and patent ductus arteriosus [Gauthier et al 2015].

ACTA2. This multisystemic smooth muscle dysfunction syndrome due to a de novo ACTA2 pathogenic variant is characterized by dysfunction of smooth muscle cells throughout the body, leading to severe and highly penetrant vascular diseases that include thoracic aortic aneurysms and aortic dissections, patent ductus arteriosus, stenosis and dilatation of cerebral vessels, mydriasis, periventricular white matter hyperintensities on MRI, and pulmonary hypertension, as well as features characteristic of ACTG2-related disorders such as hypotonic bladder and malrotation and hypo-peristalsis of the gut [Milewicz et al 2010]. Prune-belly sequence can also be associated [Richer et al 2012].

FLNA. Pathogenic variants in this X-linked gene have been reported in association with intestinal pseudoobstruction, as well as its commonly recognized phenotypes: X-linked periventricular heterotopia, a neuronal migration disorder with early lethality in affected males and seizures in affected females [Gargiulo et al 2007, Kapur et al 2010].

TYMP. Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by: progressive gastrointestinal dysmotility and cachexia manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea; ptosis/ophthalmoplegia or ophthalmoparesis; hearing loss; and demyelinating peripheral neuropathy manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities. The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades. Direct evidence of MNGIE disease is provided by increase in plasma thymidine concentration >3 µmol/L and increase in plasma deoxyuridine concentration >5 µmol/L.

SGOL1. Chronic atrial and intestinal dysrhythmia (CAID) is the constellation of sick sinus syndrome (SSS) with aberrant sinus node pacing in the heart and intestinal pseudoobstruction [Chetaille et al 2014]. Bladder involvement was not reported. Atrial dysrhythmias have not been observed in ACTG2- related disorders.

RAD21. The combination of CIPO, Barrett esophagus, and cardiac abnormalities caused by biallelic pathogenic variants in RAD21 is called Mungan syndrome [Bonora et al 2015]. Bladder involvement has not been reported. Cardiac abnormalities and Barrett esophagus have not been observed in ACTG2- related disorders.

CHRM3. Prune belly syndrome with megacystis has been reported with mutation of CHRM3, a muscarinic acetylcholine receptor subunit. Gastrointestinal symptoms were not reported [Weber et al 2005, Weber et al 2011].

CHRNA3, CHRNB2, and CHRNB4. Although these nicotinic acetylcholine receptors have not been associated with MMIHS in humans, they may be reasonable candidates based on findings in mouse [Xu et al 1999a, Xu et al 1999b].

Other Causes of Bowel Obstruction

In neonates, the clinical presentation of intestinal hypoperistalsis syndrome can mimic other causes of bowel obstruction, such as Hirschsprung disease.

Hirschsprung (HSCR) disease (or congenital intestinal aganglionosis) is characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract at birth. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine. Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis). HSCR disease may occur as an isolated finding or as part of a multisystem disorder. Affected infants frequently present in the first two months of life with findings of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. The finding in HSCR disease that distinguishes it from ACTG2-related disorders is congenital intestinal aganglionosis, characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. Additional research is needed to determine if some cases of HSCR can be caused by pathogenic variants of ACTG2.

Waardenburg syndrome type IV (WS4) is the combination of pigmentary abnormalities, hearing loss, and Hirschsprung disease [Jan et al 2008] caused by mutation of one of the following genes: EDNRB, EDN3, or SOX10. Inheritance can be either autosomal dominant (mutation of EDNRB, EDN3, or SOX10) or autosomal recessive (mutation of EDNRB or EDN3).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an ACTG2-related disorder (which can range from megacystis-microcolon-intestinal hypoperistalsis syndrome [MMIHS] to chronic intestinal pseudoobstruction [CIPO]), the following evaluations are recommended:

  • Clinical genetics consultation with complete family history
  • Urologic. Consultation with an expert in in pediatric urology whose evaluation may include studies of upper and lower urinary tract and renal function
  • Gastrointestinal. Consultation with an expert in pediatric gastroenterology whose evaluation may include radiologic studies of the gastrointestinal tract based on the symptoms and onset. Of note, most individuals with an ACTG2-related disorder will have undergone extensive radiographic imaging prenatally and/or in the neonatal period including evaluation for gastrointestinal distention and/or microcolon. However, if not performed at the time of diagnosis, studies to clarify the extent of disease could include abdominal x-rays, abdominal CT, transit studies (i.e., small bowel contrast studies), and/or endoscopy. Manometry (which typically shows reduced or absent contractions) can be used as an adjunct in the evaluation to quantify the degree of hypoperistalsis and extent of gastrointestinal dysfunction [Ambartsumyan & Rodriguez 2014].
  • Nutrition. Consultation with a specialist in pediatric nutrition that includes plotting of height and weight on standardized growth charts and assessments of dietary intake, body mass index, and nutritional status (measurement of albumin and prealbumin, and tests of liver function)

Treatment of Manifestations

Children with an ACTG2-related disorder require multidisciplinary management with specialists in pediatric gastroenterology, nutrition, urology, surgery, clinical genetics, and occupational therapy, among others. Adults with an ACTG2-related disorder require similar multidisciplinary care.

Treatment for ACTG2-related disorders remains supportive.

Urologic manifestations. Management of bladder dysfunction by an urologist is recommended.

A clear link has been established between fetal urinary tract dilation such as megacystis and long-term impairment of renal function [Al-Hazmi et al 2012]. Patients are frequently dependent on bladder management with diversion, catheterization, and/or voiding schedules. In addition, clean and safe practices in the use of indwelling intravenous catheters and bladder catheterization can help prevent infections.

In a review of 14 patients with visceral myopathy evaluated prior to the discovery of ACTG2, Ghavamian et al [1997] noted that clean intermittent catheterization decreased the frequency of urinary tract infection and observed that surgical approaches (construction of a catheterizable channel or a vesicostomy) were also therapeutic options.

In a review of 39 children with CIPO reported before the discovery of ACTG2, Lapointe et al [2002] identified megacystis in 26 and hydronephrosis in 14. They noted that urologic intervention to ensure adequate bladder emptying was important to reduce the risk of urinary tract infections and to preserve long-term renal function. Urologic treatment (at some point in their care) included voiding with abdominal pressure (14 children), intermittent catheterization (10), and antibiotic prophylaxis (17).

Gastrointestinal manifestations. Management by a gastroenterologist and nutritionist familiar with intestinal motility disorders is recommended. Patients are frequently dependent on total parenteral nutrition (TPN) (see review by Gabbard & Lacy [2013]).

Complications of long-term TPN can be progressive and include irreversible cholestasis, hepatic dysfunction, central line infections, and thromboembolic events. For this reason, individuals with an intestinal disorder that requires long-term TPN (like those seen in ACTG2-related disorders) have undergone multi-visceral transplantation including liver and intestine. In the series of Gosemann & Puri [2011] in which 12 individuals underwent such multivisceral transplants, TPN could be discontinued in the majority; however, bladder catheterization was still required.

Isolated intestinal transplantation has also been reported in one individual with MMIHS [Huang et al 2013a].

Of note, use of pro-kinetic agents such as 5HT4 agonists has resulted in anecdotal evidence of improvement in bowel function [Lehtonen et al 2012, Wangler et al 2014], as well as failure to improve in bowel function in MMIHS [Hiradfar et al 2013] and some cases of molecularly confirmed ACTG2-related MMIHS [Wangler et al 2014].

Prevention of Secondary Complications

Establishing the correct diagnosis of an ACTG2-related disorder may help avoid unnecessary exploratory laparotomies for unexplained episodes of apparent intestinal obstruction (i.e., CIPO).

Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period.

Clean and safe practices in the use of indwelling intravenous catheters for administration of TPN and bladder catheterization can help prevent infections.

Surveillance

Surveillance should be individualized using a multidisciplinary approach.

Surveillance should take into account the link between fetal urinary tract dilation and long-term increased risk for impaired renal function [Al-Hazmi et al 2012].

Long-term dependence on parenteral nutrition requires routine surveillance of liver function.

Agents/Circumstances to Avoid

For those with CIPO, high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [Gabbard & Lacy 2013].

No drugs are known to exacerbate the smooth muscle functional defect in ACTG2-related disorders.

Evaluation of Relatives at Risk

Using molecular genetic testing for the ACTG2 pathogenic variant identified in an affected family member, it is appropriate to evaluate relatives at risk as early diagnosis may help prevent unnecessary surgery for symptoms of intestinal obstruction and may allow early evaluation of bladder and renal function, and the urinary tract for evidence of dilation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

When a fetus at risk for an ACTG2-related disorder has evidence of bladder distention on prenatal ultrasound examination, consultation with a maternal fetal medicine specialist is recommended. Of note, in some fetuses with prenatal detection of megacystis, vesicoamniotic shunts have been performed. The rationale for this has been questioned [Tuzovic et al 2014].

Among the limited number of mothers with an ACTG2-related disorder reported, some instances of poor labor progression and weak uterine contractions have been noted [Klar et al 2015].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ACTG2-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with an ACTG2-related disorder have an affected parent. Among 23 probands reported to date, six had an affected parent [Lehtonen et al 2012, Wangler et al 2014, Klar et al 2015].
  • A proband with an ACTG2-related disorder may have the condition as the result of a de novo pathogenic variant. Among the 23 probands reported to date, 14 had a de novo pathogenic variant [Holla et al 2014, Thorson et al 2014, Wangler et al 2014, Tuzovic et al 2015]. In two other probands it was unknown if the pathogenic variant was de novo or inherited.
  • If the ACTG2 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent (observed in one of the 23 families reported to date [Tuzovic et al 2015]).
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination, a medical history with emphasis on signs of intestinal obstruction as an infant and/or chronic constipation, and molecular genetic testing.
  • The family history of some individuals diagnosed with an ACTG2-related disorder may appear to be negative because of a milder phenotypic presentation, failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: If the parent is the individual in whom the ACTG2 pathogenic variant first occurred s/he may have somatic mosaicism for the ACTG2 pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • Although penetrance of ACTG2-related disorders appears to be complete, the severity of clinical findings can vary within a family [Lehtonen et al 2012, Klar et al 2015].
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the ACTG2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism (observed in one of the 23 families reported to date [Tuzovic et al 2015]).

Offspring of a proband. Each child of an individual with an ACTG2-related disorder has a 50% chance of inheriting the pathogenic variant. Although penetrance of ACTG2-related disorders appears to be complete, the severity of clinical findings can vary within a family.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the ACTG2 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ACTG2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for an ACTG2-related disorder are possible. Note, however, that clinical severity cannot be accurately predicted by family history or molecular genetic testing.

Although affected individuals are intellectually normal, ACTG2-related disorders can be severe (e.g., MMIHS) and families may seek prenatal diagnosis. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Foundation for Functional Gastrointestinal Disorders (IFFGD)
    PO Box 170864
    Milwaukee WI 53217-8076
    Phone: 888-964-2001 (toll-free); 414-964-1799
    Fax: 414-964-7176
    Email: iffgd@iffgd.org
  • International Foundation for Functional Gastrointestinal Disorders (IFFGD) - Pediatric
    PO Box 170864
    Milwaukee WI 53217-8076
    Phone: 888-964-2001 (toll-free); 414-964-1799
    Fax: 414-964-7176
    Email: iffgd@iffgd.org
  • National Digestive Diseases Information Clearinghouse (NDDIC)
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    31 Center Drive
    Building 31, Room 9A06
    MSC 2560
    Bethesda MD 20892-2560
    Phone: 301-496-3583
  • Prune Belly Syndrome Network
    P.O. Box 16071
    Philadelphia PA 19154
    Phone: 855-ASK-PBSN
  • Pull-thru Network (PTN)
    2312 Savoy Street
    Hoover AL 35226-1528
    Phone: 205-978-2930
    Email: PTNmail@charter.net

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ACTG2-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ACTG2-Related Disorders (View All in OMIM)

102545ACTIN, GAMMA-2, SMOOTH MUSCLE, ENTERIC; ACTG2
155310VISCERAL MYOPATHY; VSCM

Gene structure. ACTG2 spans approximately 27 kb and has a total of nine exons, eight of which are coding. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date all the pathogenic variants reported in ACTG2-related disorders are missense variants. Many of these affect arginine residues.

Normal gene product. ACTG2 encodes γ-2 actin, an enteric actin protein.

Abnormal gene product. The abnormal proteins are hypothesized to affect actin filament polymerization and smooth muscle contraction [Thorson et al 2014]. Aggregation of the γ-2 actin molecules may also occur [Lehtonen et al 2012]. Structural data on actin molecules support the role of some of the mutated amino acids in actin polymerization [Graceffa & Dominguez 2003].

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Chapter Notes

Author Notes

Web pages

Authors’ research. The authors are currently using the latest technology including exome sequencing to understand rare Mendelian disorders including disorders of intestinal motility.

Revision History

  • 11 June 2015 (me) Review posted live
  • 15 July 2014 (mw) Original submission
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