Cacha M. P. C. D. Peeters-Scholte

Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI.

Mutations in the gene COL4A1, encoding collagen IV A1, are associated with familial porencephaly. Previously, COL4A1 mutation-associated antenatal hemorrhages have been suggested by early post-natal imaging. We describe 2 children with fetal intracerebral hemorrhages and a COL4A1 mutation. There was also extensive hemispheric tissue loss in both infants and loss of cerebellar tissue in one infant. This paper show prenatal evidence of fetal hemorrhage in association with a COL4A1 mutation.

Fetal brain imaging in isolated congenital heart defects – a systematic review and meta‐analysis

Congenital heart defects (CHDs) are associated with neurodevelopmental (ND) delay. This study aims to assess evidence for impaired prenatal brain development, in fetuses with CHD. A systematical search was performed, and 34 studies evaluating the fetal brain [magnetic resonance imaging (MRI) or ultrasound] in isolated CHD were included (1990–2015). Data regarding cerebral abnormalities, head circumference growth and middle cerebral artery flow were extracted. Prenatal MRI was studied in ten articles (445 fetuses), resulting in a pooled prevalence of 18% (95%CI −6%; 42%) for combined structural and acquired cerebral abnormalities. Prenatal head circumference was studied in 13 articles (753 fetuses), resulting in a pooled z‐score of −0.51 (95%CI −0.84; −0.18). Doppler was studied in 21 articles (1412 fetuses), resulting in a lower middle cerebral artery pulsatility index (z‐score −0.70 95%CI −0.99; −0.41) in left‐sided CHD only. We conclude that prenatal MRI and ultrasound demonstrate brain abnormalities, delay in head growth and brainsparing in subgroups of CHD. However, large MRI studies are scarce, and ultrasound data are biased towards severe and left‐sided CHD. Long‐term follow‐up studies correlating prenatal findings with postnatal ND outcome are limited, and data are lacking to support counseling families regarding ND outcome based on prenatal findings suggestive of altered brain development.

Increased concentrations of both NMDA receptor co-agonists d-serine and glycine in global ischemia: a potential novel treatment target for perinatal asphyxia

Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-d-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia–ischemia, but the role of both endogenous NMDAr co-agonists d-serine and glycine remains largely elusive. We investigated d-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia–ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and d-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from l-serine. Upon reperfusion glycine concentrations normalized and d-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased d-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition.

GPSM2 and Chudley–McCullough Syndrome: A Dutch Founder Variant Brought to North America

Chudley–McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.

Clinical and molecular characterization of an infant with a tandem duplication and deletion of 19p13.

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP‐array and confirmed by fluorescence in situ hybridization. Mate‐pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.

Nitric Oxide Synthase Inhibition as a Neuroprotective Strategy Following Hypoxic–Ischemic Encephalopathy: Evidence From Animal Studies

Background Hypoxic–ischemic encephalopathy following perinatal asphyxia is a leading cause of neonatal death and disability worldwide. Treatment with therapeutic hypothermia reduced adverse outcomes from 60 to 45%. Additional strategies are urgently needed to further improve the outcome for these neonates. Inhibition of nitric oxide synthase (NOS) is a potential neuroprotective target. This article reviews the evidence of neuroprotection by nitric oxide (NO) synthesis inhibition in animal models. Methods Literature search using the EMBASE, Medline, Cochrane, and PubMed databases. Studies comparing NOS inhibition to placebo, with neuroprotective outcome measures, in relevant animal models were included. Methodologic quality of the included studies was assessed. Results 26 studies were included using non-selective or selective NOS inhibition in rat, piglet, sheep, or rabbit animal models. A large variety in outcome measures was reported. Outcome measures were grouped as histological, biological, or neurobehavioral. Both non-selective and selective inhibitors show neuroprotective properties in one or more outcome measures. Methodologic quality was either low or moderate for all studies. Conclusion Inhibition of NO synthesis is a promising strategy for additional neuroprotection. In humans, intervention can only take place after the onset of the hypoxic–ischemic event. Therefore, combined inhibition of neuronal and inducible NOS seems the most likely candidate for human clinical trials. Future studies should determine its safety and effectiveness in neonates, as well as a potential sex-specific neuroprotective effect. Researchers should strive to improve methodologic quality of animal intervention studies by using a systematic approach in conducting and reporting of these studies.

Neuroprotectieve behandelingsstrategieën na perinatale hypoxie-ischemie

SummaryPerinatal hypoxia-ischemia is an important cause of neonatal mortality and morbidity (encephalopathy and mental retardation). A substantial part of the perinatal hypoxic-ischemic-related brain damage occurs upon and after reperfusion and reoxygenation by production of excitotoxic neurotransmitters and free radicals, by excessive nitric oxide production, cytokines release and a decrease in the endogenous production of growth factors. The presence of a so-called therapeutic window between the moment of hypoxia-ischemia and the start of cell death provides the opportunity to intervene both therapeutically as well as non-therapeutically. This article provides general information about the mechanisms that lead to brain damage following perinatal hypoxia-ischemia. Potential therapeutical interventions following perinatal hypoxia-ischemia are discussed, categorized to their mode of action. Furthermore, some non-therapeutical interventions are discussed, such as hypothermia and hyperbaric oxygen therapy. Well designed combinations of neuroprotective agents with non-therapeutical interventions should be given consideration in the treatment of post hypoxic-ischemic reperfusion injury of the newborn brain.SamenvattingPerinatale hypoxie-ischemie is een belangrijke oorzaak van neonatale mortaliteit en morbiditeit (spasticiteit en mentale retardatie). Een groot deel van de hierbij opgelopen hersenschade ontstaat gedurende en na reperfusie en reoxygenatie door de productie van exciterende neurotransmitters en vrije radicalen door overmatige stikstofmonoxideproductie, het vrijkomen van cytokinen en een afname in de endogene groeifactorenproductie. Het bestaan van een kritische tussenfase tussen het moment van hypoxie-ischemie en het optreden van celdood creëert mogelijkheden om zowel medicamenteus als niet-medicamenteus te interveniëren. Dit artikel geeft informatie over de mechanismen die leiden tot hersenschade na perinatale hypoxie-ischemie. Vervolgens wordt beknopt ingegaan op mogelijke medicamenteuze interventiestrategieën om de post-hypoxisch-ischemische reperfusieschade aan de hersenen te voorkomen of te reduceren. Ten slotte worden enkele niet-medicamenteuze interventies besproken, te weten hypothermie en het gebruik van hyperbare zuurstoftherapie. Een combinatie van medicamenteuze en niet-medicamenteuze interventies is het meest veelbelovend om neuroprotectie te kunnen bewerkstelligen na perinatale hypoxie-ischemie.

Putting genome-wide sequencing in neonates into perspective

PurposeSeveral studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population.MethodsWe retrospectively evaluated all genetic NICU consultations in a 2-year period.ResultsIn 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients.ConclusionsOur study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.