Disruption of normal intrauterine brain development is a significant consequence of premature birth and may lead to serious complications, such as neonatal brain injury (NBI). This prospective case-control longitudinal study aimed at determining the levels and prognostic value of serum activin A during the first three days of life in human premature neonates which later developed NBI. It was conducted in a single tertiary hospital and eligible participants were live-born premature (<34 weeks) neonates. Each case (n = 29) developed NBI in the form of an intraventricular haemorrhage, or periventricular leukomalacia, and was matched according to birth weight and gestational age to one neonate with normal head ultrasound scans. Serum activin A levels in both groups showed a stable concentration during the first three days of life as no difference was observed within the two groups from the first to the third day. Neonates diagnosed with NBI had significantly higher activin A levels during the first two days of life compared to control neonates and its levels correlated to the severity of NBI during the second and third day of life. Although serum activin A on the second day was the best predictor for neonates at risk to develop NBI, the overall predictive value was marginally fair (area under the ROC-curve 69.2%). Activin A, in combination with other biomarkers, may provide the first clinically useful panel for the early detection of premature neonates at high risk of NBI.

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine-Serine rich domain and causing the hyper-activation of the receptor and the responsivity to the non-canonical ligand, Activin A. In the present study, we described a 3-years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution.
METHODS: Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection-based assays.
CONCLUSIONS: We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A-mediated signaling, as observed for the gene variants associated with FOP.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare inherited disease characterized by progressive heterotopic ossification. Disease onset, severity and symptoms vary between FOP patients, as does the frequency and activity of so-called flare-ups, during which tendons, ligaments, muscle and soft tissue are replaced by bone. Traumata, infections or other stressors are known inducers of flare-ups, and the hormone Activin A may be involved in disease activity; however, reliable biomarkers for FOP activity are missing, and the basal trace element and inflammatory state of patients are unknown. We hypothesized that FOP patients develop characteristic deficiencies in inflammation-related trace elements and display a chronically increased inflammatory cytokine level, collectively aggravating disease course and flare-up risk. Serum samples from 15 FOP patients and 25 relatives were collected under highest quality standards. Concentrations of Cu, Se and Zn were determined by total reflection X-ray fluorescence, and 27 cytokines along with Activin A by specific antibody-based techniques. Data were tested for normal distribution and analyzed by parametric or non-parametric tests. Concentrations of Se and Cu were not different between the groups, while Zn levels were slightly higher in FOP as compared to controls (1110±251 vs. 970±176ng/ml, P=0.04). The average concentrations of cytokines and Activin A were not different. When focusing on the two patients with self-reported flare-ups, again no obvious differences were noted. The cytokines Eotaxin, G-CSF, hbFGF and TNF-α were within the upper half of measured concentrations, and may warrant further longitudinal analyses. Our data do not support the hypothesis that FOP patients display a characteristic pattern of trace elements or have a generally increased tone of pro-inflammatory cytokines.