ACTG2 Visceral Myopathy

Excerpt

Clinical characteristics: ACTG2 visceral myopathy is a disorder of smooth muscle dysfunction of the bladder and gastrointestinal system with phenotypic spectrum that ranges from mild to severe. 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. Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, megacystis microcolon intestinal hypoperistalsis syndrome, and chronic intestinal pseudoobstruction (CIPO) in neonates at the more severe end to intermittent abdominal distention and functional intestinal obstruction at the milder end.

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 ACTG2 visceral myopathy is established in a proband with suggestive findings and a heterozygous ACTG2 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations. Treatment is supportive. Specialized centers offer multidisciplinary medical and surgical models of care including comprehensive TPN management and multivisceral transplantation. 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. Bowel dysfunction, microcolon, intestinal dysmotility, and associated gastrointestinal comorbidities typically require management by a gastroenterologist and nutritionist familiar with intestinal motility disorders.

Surveillance: Surveillance should be individualized using a multidisciplinary approach.

For bladder and urinary tract comorbidities, monitor voiding, urinary tract anatomy, and renal function.

For intestinal manifestations, monitor nutritional status and possible TPN-associated complications (line infections, liver disease) and consider need for multivisceral or isolated intestinal transplantation.

Agents/circumstances to avoid: Treatment/medications (including opioids) to be avoided or limited include those that diminish bowel and bladder motility.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of relatives at risk as early diagnosis may help prevent unnecessary surgery for manifestations of intestinal obstruction and may allow early evaluation of bladder and renal function, and of the urinary tract for evidence of dilatation.

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

Genetic counseling: ACTG2 visceral myopathy is typically inherited in an autosomal dominant manner. (Apparent autosomal recessive inheritance, suggested in one family, is not discussed further in the Summary.)

Approximately 73% of individuals with ACTG2 visceral myopathy have a de novo pathogenic variant.

If a parent is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although penetrance of ACTG2 visceral myopathy appears to be complete, the severity of clinical findings can vary between heterozygous family members.

Each child of an individual with ACTG2 visceral myopathy has a 50% chance of inheriting the pathogenic variant.

Once the ACTG2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.