COL4A2 mutation associated with familial porencephaly and small-vessel disease.

Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

DTI reveals network injury in perinatal stroke.

BACKGROUND: Previous research showed acute diffusion-weighted imaging changes in pulvinar after extensive cortical injury from neonatal stroke. The authors used diffusion tensor imaging (DTI) to see how separate regions of ipsilateral thalamus are directly affected after a primary hit to their connected cortex in neonatal stroke. METHODS: The authors analysed DTI images of three term infants with acute unilateral cortical arterial ischaemic stroke. Probabilistic tractography was used to define separate thalamic regions of interests (ROIs). The authors evaluated the three eigenvalues (EV) and apparent diffusion coefficient (ADC) values in the ROIs. RESULTS: The ADC and EV in voxels of ROIs placed within the nuclei corresponding to ischaemic cortex were significantly lower than those in the unaffected contralesional thalamic nuclei. CONCLUSIONS: Our findings support the concept of acute network injury in neonatal stroke. ADC and EV were altered in specific thalamic regions that corresponded to the specific cortical areas affected by the primary ischaemic injury.

Subcortical structures and the neurobiology of infant attachment disorganization: a longitudinal ultrasound imaging study.

Attachment disorganization in infancy is a risk factor for behavior problems and other psychopathology. Traditionally the role of parental behavior for qualitative differences in early attachment relationships has been emphasized. However, disrupted infant-parent interactions only partly explain attachment disorganization. A complementary focus on child factors such as early differences in the underlying neurobiological systems is needed. We examined whether early structural differences in the gangliothalamic ovoid, comprising the basal ganglia and the thalamus, are involved in the etiology of infant attachment disorganization. Gangliothalamic ovoid diameter was measured by ultrasound in 6-week-old participants of a prospective population-based cohort study. Attachment classification of 629 of these infants was assessed with the strange situation at 14 months of age. Neurobiological differences within the normal range were prospectively associated with attachment disorganization. Infants with a larger gangliothalamic ovoid at 6 weeks had a lower risk of attachment disorganization at 14 months (OR = 0.73 per SD increase in diameter, 95% CI 0.57-0.93, p < .05). Volume of the lateral ventricles as an index of general brain development was not associated with attachment disorganization. These findings provide new insight into the etiology of infant attachment disorganization that may in part be neurodevelopmentally determined.

Apnoea in relation to neonatal temporal lobe haemorrhage.

BACKGROUND: Six term newborns presented with apnoea and temporal lobe haemorrhage. AIM: In this observational study, we described involvement of the limbic system in apnoeic term newborns with temporal lobe injury. METHODS: Six term newborns presented to the neonatal care unit with apnoea within the first 2 days of life. Ultrasound (US) and MRI of the brain were obtained in the first week of life. RESULTS: Apnoea was related to temporal lobe haemorrhage in all. During apnoeic periods four had focal epileptic activity on EEG. All lesions were detected first with US. On MRI, haemorrhages were located in the parenchyma, the subdural and/or subarachnoid space. Three haemorrhages were surrounded by infarction in the temporal lobe. In three infants hippocampus and mesial temporal cortex were affected. In two basal temporal cortex only was involved. Vascular anomalies were excluded by MRA, serial MRI or serial US with Doppler imaging. CONCLUSION: Term infants with seizure associated apnoea may present with haemorrhage and/or infarction to hippocampus, mesial and basal temporal cortex. This study supports the existence and possible disruption of descending influences from the temporal cortex and/or amygdala on brainstem breathing centres in the term newborn.

Cerebral ventricular volume and temperamental difficulties in infancy. The Generation R Study.

BACKGROUND: Numerous studies have provided evidence for subtle deviations in brain morphology in children with psychiatric disorders, but much less is known about the onset and developmental trajectory of these deviations early in life. We sought to determine whether variances in cerebral ventricular size in fetuses and newborns are associated with temperamental difficulties in infants. METHODS: Within a population-based cohort study, we measured the size of the lateral ventricle of the fetus' brain twice during pregnancy. We used 3-dimensional cranial ultrasound to measure the cerebral ventricular volume of infants at age 6 weeks. We then related the size of the cerebral ventricular system to temperamental dimensions at age 3 months using the Mother and Baby Scales, and at age 6 months using the Infant Behavior Questionnaire for a total of 1028 infants. RESULTS: The size of the lateral ventricle of the fetuses in midpregnancy was not related to temperamental difficulties in infants; however, smaller lateral ventricles in late pregnancy were associated with higher activity levels at the age of 6 months. Infants with smaller ventricular volumes at age 6 weeks experienced higher activity levels, more anger or irritability and poorer orienting later in infancy. Children with the lowest ventricular volumes scored on average 0.15 (95% confidence interval 0.06-0.23, p = 0.001) points higher (23%) on activity levels than children with the highest ventricular volumes. CONCLUSION: Variations in ventricular size before and shortly after birth are associated with temperamental difficulties. Some of the morphologic differences between children with and without psychiatric disorders may develop very early in life.

Foetal growth determines cerebral ventricular volume in infants The Generation R Study.

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (beta=0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.

Extensive cerebral infarction in the newborn due to incontinentia pigmenti.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal multisystem disorder characterized by skin lesions following Blaschko lines. In almost all patients the skin is involved and in 30-50% the central nervous system (CNS) is. Vascular occlusive phenomena probably play a role in CNS involvement. Whether these vascular changes are based on macro- or microvascular disease in the neonatal presentation is not fully understood. PATIENTS AND METHODS: We describe two patients with IP with neonatal seizures related to cerebral infarction. In comparison, we reviewed reports of ischaemic cerebrovascular injury in neonatal IP. RESULTS: No descriptions of documented large artery occlusion in neonatal IP was found in the literature. One of our patients showed striatal arteriopathy, never described before in IP. Extensive injury in one of our cases was heterogeneous, mixing healthy with diseased areas within large arterial fields. CONCLUSIONS: We postulate that neonatal cerebral infarction in IP is a macrovascular disorder of medium sized or small arteries. The pattern of arterial involvement might follow hypothetical brain Blaschko lines. The extent of cerebral involvement probably results from genetic mosaicism in which Lyonisation leads to endothelial apoptosis, similar to the process in the skin.

Bacillus cereus meningoencephalitis in preterm infants: neuroimaging characteristics.

BACKGROUND AND PURPOSE: Meningoencephalitis can severely damage the developing brain. Preterms are more prone for nosocomial infections with pathogens other than Group B streptococci and Escherichia coli. In this report we focus on the deleterious clinical course and imaging characteristics of proven Bacillus cereus meningoencephalitis. METHODS: We collected 3 cases of proven Bacillus cereus meningoencephalitis. In the medical records we focused on prenatal, perinatal, and postnatal risk factors. Imaging data of several brain ultrasounds, MR images, and diffusion-weighted images were reevaluated. RESULTS: The ultrasound and MR images show a typical pattern of mainly hemorrhagic and early cavitating, selective white matter destruction. CONCLUSION: Knowledge of this paradigm of acquired brain injury may help to better understand the natural course of these severe neonatal infections.