ACTG2 variants discovered as a reliable diagnostic marker and prognostic tool for visceral myopathy

Visceral myopathy is a rare disorder of smooth muscle dysfunction that manifests in a broad range of symptoms ranging from severe gastrointestinal and genitourinary dysfunction requiring surgical and nutritional interventions in newborns to mild gastrointestinal issues in adults. The wide spectrum of symptoms, some of which overlap with other common GI complaints, makes the diagnosis and clinical management of this disorder particularly challenging. An international research team led by Dr. Michael Wangler, assistant professor at Baylor College of Medicine, clinical geneticist and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, performed an in-depth clinical and genomic analysis which revealed ACTG2 gene as the primary determinant of severe symptoms and worse long-term prognosis in majority of the patients. Furthermore, patients with severe symptoms had a higher likelihood of mutations that substituted key arginine residues in ACTG2, while patients with milder symptoms either had no mutations or had non-arginine mutations in this gene. Finally, they established a robust scale that correlates each arginine mutation to disease severity, a promising finding that could potentially be utilized for diagnostic and prognostic purposes. The study was published in the journal Human Mutation.

Depending on the age of onset and symptom severity, patients with this disorder often end up receiving varying diagnosis of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS), chronic intestinal pseudo-obstruction (CIPO), hollow visceral myopathy. Fifty-three MMIHS patients from all over the world were enrolled in the study that was conducted at Baylor College of Medicine and Texas Children’s Hospital over two periods that spanned several years. While a previous study by Wangler and others identified ACTG2 as one of the causative genes, this is the first large-scale genomic study of MMIHS patients. The study establishes variations in ACTG2 as the primary determinant of majority (75-90%) of the medically complex disease features and complications seen in MMIHS patients. Patients that tested positive for ACTG2 mutations had a significantly higher chance of poor outcomes and severe symptoms. Furthermore, substitutions in five arginine sites accounted for almost 80% of ACTG2-positive cases and nearly 50% of all the cases in this cohort.

ACTG2 gene encodes actin, a protein that forms microfilaments and together with the motor protein, myosin, is responsible for the contraction and relaxation of smooth muscles. Due to changes in ACTG2 gene, the smooth muscles in the guts and sometimes, the bladder, of MMIHS patients are unable to function properly – they cannot contract or move the food and fluids to the correct compartments, which results in severe malnutrition and bladder dysfunction. Depending on the type of mutation and disease severity, the symptoms may onset prenatally, at birth or later, in adulthood. In the most severe forms, the fetus has an enlarged bladder which is dysfunctional at birth - the baby may not be able to feed at all; even the bile does not track down to their lower GI tract. On the other hand, patients with milder symptoms may have pseudo-obstruction and GI motility issues that resemble more common disorders such as irritable bowel syndrome.

“A few decades back, MMIHS used to be a fatal at birth. Since the advent of total parenteral nutrition (TPN) in the 1970’s, patients with severe MMIHS are able to survive longer. But as one can imagine, it is a difficult situation because complete dependence on intravenous nutrition causes long-term damage to their liver. Most patients on TPN end up needing gut-liver transplants. Based on our study, we strongly recommend MMIHS patients with severe GI/genitourinary symptoms to first undergo targeted sequencing of ACTG2 gene to determine if they have any variants and if so, whether it is an arginine or non-arginine substitution and finally, identify the specific arginine variant they carry – this data will provide clinicians with a clearer picture of that particular patient’s disease trajectory, and guide the personalized clinical care and genetic counseling support they receive. This study is a perfect example of how genomics can be used to tackle complex medical problems to improve patient outcomes,” Wangler said.