Alexandra Zecic

Mutation of TBCE causes hypoparathyroidism- retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad–Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations1,2,3. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny–Caffey syndrome4 (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43–44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation7. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of α-tubulin subunits and the formation of α–β-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad–Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny–Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43–44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of α-tubulin subunits and the formation of α–β-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Effect of Treatment of Subclinical Neonatal Seizures Detected With aEEG: Randomized, Controlled Trial

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

Perinatal cortical infarction within middle cerebral artery trunks

AIM To define neonatal pial middle cerebral artery infarction. METHODS A retrospective study was made of neonates in whom focal arterial infarction had been detected ultrasonographically. A detailed study was made of cortical middle cerebral artery infarction subtypes. RESULTS Forty infarctions, with the exception of those in a posterior cerebral artery, were detected ultrasonographically over a period of 10 years. Most were confirmed by computed tomography or magnetic resonance imaging. Factor V Leiden heterozygosity was documented in three. The onset was probably antepartum in three, and associated with fetal distress before labour in one. There were 19 cases of cortical middle cerebral artery stroke. The truncal type (n=13) was more common than complete (n = 5) middle cerebral artery infarction. Of six infarcts in the anterior trunk, four were in term infants and five affected the right hemisphere. Clinical seizures were part of the anterior truncal presentation in three. One of these infants, with involvement of the primary motor area, developed a severe motor hemisyndrome. The Bayley Mental Developmental Index was above 80 in all of three infants tested with anterior truncal infarction. Of seven patients with posterior truncal infarction, six were at or near term. Six of these lesions were left sided. Clinical seizures were observed in three. A mild motor hemisyndrome developed in at least three of these infants due to involvement of parieto-temporal non-primary cortex. CONCLUSIONS Inability to differentiate between truncal and complete middle cerebral artery stroke is one of the explanations for the reported different outcomes. Severe motor hemisyndrome can be predicted from neonatal ultrasonography on the basis of primary motor cortex involvement. Clinical seizures were recognised in less than half of the patients with truncal infarction; left sided presentation was present in the posterior, but not the anterior truncal type of infarction. Asphyxia is a rare cause of focal arterial infarction.

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders

Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. Objectives: The aim of this study was to analyse complications and outcome after implementation. Methods: Data were retrieved from an online database to which all centres had contributed. Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

Network injury to pulvinar with neonatal arterial ischemic stroke.

The purpose of this study is to establish that newborn stroke involving extensive parts of cerebral cortex immediately leads to secondary network injury in pulvinar. Seven term infants with cortical stroke presented with hypersignal in pulvinar on DWI. Stroke types included: complete MCA stroke (n=4); PCA stroke, ICA stroke and multiple artery stroke (1 each). Age range at scanning was between day 2 and 6 after birth (except for 1 infant scanned within 7 days of acute presentation during ECMO). ADC values in secondarily injured pulvinar were significantly higher than in the area with primary (sub)cortical injury (all patients scanned with identical MR image acquisition). In the absence of asphyxia and because pulvinar is outside of the primary area of infarction, we conclude that there are suggestions from imaging for acute secondary injury to pulvinar following primary damage of their cortical targets and/or connecting axons. Acute secondary injury is probably due to excitotoxicity and deafferentiation. The relevance of network injury for prognosis and the impact of early treatment on it have yet to be studied, in stroke but also in other acute perinatal brain disorders.

Transplacental passage of a nonionic contrast agent

We report the presence of iopromide in the bowel and urine of a preterm infant, born 10 days after intravenous administration of the nonionic monomer to his mother. Excessive urinary iodine excretion and borderline hyperthyrotropinaemia were observed in the infant. Moreover, crossing of the fetal blood-brain barrier was demonstrated by detection of the angiographic material in CSF and thus direct fetal neurotoxic effects cannot be excluded. Conclusion:These widely used contrast media may cross the placenta and accumulate in various fetal tissues in significant amounts causing possible neonatal toxicity. Therefore the perinatal safety of these diagnostic agents should at least be questioned.

Imaging patterns of brain injury in term‐birth asphyxia

Aim: To develop an extended asphyxia‐score based on cerebral ultrasound (US) and MRI in order to gain further insight into the pathophysiology of asphyxia.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia

AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.

Evidence for autosomal dominant inheritance in prenatally diagnosed CHAOS.

Congenital high airway obstruction syndrome (CHAOS) is a rare prenatal diagnosis consisting of a typical fetal triad of large hyperechogenic lungs, flattened or inverted diaphragms and ascites. Most cases are sporadic with unknown incidence. Before attempts of fetoscopic fetal salvage or ex utero intrapartum treatment (EXIT) are considered, additional malformations must be carefully excluded as CHAOS may be part of various monogenic conditions or chromosomal disorders. We report an unique family with autosomal dominant inheritance of CHAOS and variable expression in the affected father and two affected children. It is concluded that minor expression in one of the parents may be an important indicator for genetic counseling in CHAOS and management of future pregnancies.

Neonatal infarction within basal cerebral vein territory.

In this report, an unusual intracranial haemorrhage in a term male infant born to a mother with diabetes is explained on the basis of occlusion of both basal veins of Rosenthal. This diagnosis relies on anatomical location and iconographic aspect of the clots. Evidence that this vessel is occluded cannot be ascertained from ultrasound or MR angiographic techniques in the neonatal period. The basal vein has not been implicated in previous reports of neonatal brain haemorrhage.