Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy. K E Y W O R D SACTG2, dysmotility, megacystis-microcolon intestinal hypoperistalsis, smooth muscle, visceral myopathy

Background: The high cerebral morbidity of premature neonates is thought to be related to changes in tissue perfusion in vulnerable areas of the brain. Quantification of power Doppler (PD) images using the index fractional moving blood volume (FMBV) may allow measurement of regional cerebral perfusion. Objective: To evaluate the reproducibility of calculating FMBV using PD ultrasound images to estimate cerebral perfusion. Methods: Two experienced clinicians performed head ultrasounds on 24 normally-grown neonates at less than 33 weeks’ gestation. Both clinicians independently acquired and stored three PD images in two different coronal planes. FMBV was calculated offline after selecting two predefined regions of interest within these planes (basal ganglia and subependymal regions). Reproducibility was evaluated by calculating the intraclass correlation coefficient (intraCC) and the interclass correlation coefficient (interCC). Results: FMBV was successfully evaluated in 24/24 neonates by both clinicians. The intraCC for repeatability for observer A was 1.00 (95% CI 1.00–1.00) for the basal ganglia and 0.99 (95% CI 0.99–1.00) for the subependymal region, and for observer B was 0.99 (95% CI 0.99–1.00) for the basal ganglia and 0.96 (95% CI 0.92–0.98) for the subependymal region. The interCC was 0.86 (95% CI 0.68–0.94) for the basal ganglia and 0.93 (95% CI 0.86–0.97) for the subependymal region. Conclusion: Using standardised settings and a well-defined region of interest, the calculation of FMBV using PD images is a reproducible method of estimating neonatal regional cerebral perfusion.

Background: Infants with extremely low birth weight uniformly develop anemia of prematurity and frequently require red blood cell transfusions (RBCTs). Although RBCT is widely practiced, the indications remain controversial in the absence of conclusive data on the long-term effects of RBCT. Objectives: To summarize the current equipoise and to outline the study protocol of the ‘Effects of Transfusion Thresholds on Neurocognitive Outcome of extremely low birth-weight infants (ETTNO)’ study. Methods: Review of the literature and design of a large pragmatic randomized controlled trial of restrictive versus liberal RBCT guidelines enrolling 920 infants with birth weights of 400–999 g with long-term neurodevelopmental follow-up. Results and Conclusions: The results of ETTNO will provide definite data about the efficacy and safety of restrictive versus liberal RBCT guidelines in very preterm infants.

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