Segregation of a Missense Variant in Enteric Smooth Muscle Actin γ-2 With Autosomal Dominant Familial Visceral Myopathy

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution

“…IV:2) showed a normal ACTG2 staining without degeneration or fibrosis of the muscle layers. Abnormal intracellular inclusions and slightly reduced ACTG2 staining have been reported in intestinal muscle layers of some FVM patients, 14 but this was not observed in our case from the analysis of one specimen. The normal histology in intestinal smooth muscle layers of our patient may be related to her relatively young age, the possibility of focal abnormalities as well as the limited resolution from light microscopy.…”

“…Pathogenic variants in ACTA2 are predominantly associated with vascular symptoms including familial thoracic aneurysms, 5 but may in rare cases involve visceral organs including the urinary and gastrointestinal tracts. 6,7 On the other hand, ACTG2 was recently found mutated in a family with FVM and adult gastrointestinal problems, 14 as well as in the MMIH syndrome with severe neonatal symptoms from the intestines and the urinary tract. 15,16 The family investigated in this study shows a phenotypic overlap with both FVM and the MMIH syndrome but our observations on the variable onset as well as the involvement of the bile tract and uterus add to previous reports.…”

“…10,11 The clinical variability is extensive and a severe form is the megacystis-microcolonintestinal hypoperistalsis (MMIH; MIM: 249210) syndrome with prenatal or neonatal onset of gastrointestinal obstruction and bladder enlargement. [12][13][14][15] In contrast, milder forms of enteric visceral myopathy may remain undiagnosed until adulthood. 14,16 Because of the variable symptomatology, this group of visceral myopathies constitutes a diagnostic challenge and some adult patients are referred to as chronic pseudo-obstruction, hollow visceral myopathy or pseudoHirschprung disease.…”

“…[12][13][14][15] In contrast, milder forms of enteric visceral myopathy may remain undiagnosed until adulthood. 14,16 Because of the variable symptomatology, this group of visceral myopathies constitutes a diagnostic challenge and some adult patients are referred to as chronic pseudo-obstruction, hollow visceral myopathy or pseudoHirschprung disease. 2,17 The findings on pathogenic MYH11 and ACTA2 variants in TAAD have raised the possibility that different components of the smooth muscle contractile unit and cytoskeleton may be responsible for other types of myopathies.…”

“…14 The gene encodes enteric smooth muscle actin γ-2 and the finding implied that the mechanism causing FVM is perturbed contractile function. This was confirmed by expression analysis of the c.422C4A variant showing reduced levels of the ACTG2 protein and a predicted poor actin polymerization.…”