Further refinement of COL4A1 and COL4A2 related cortical malformations.

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia. METHODS: We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly. RESULTS: One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations. CONCLUSIONS: Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.

A case of tubulinopathy presenting with porencephaly caused by a novel missense mutation in the TUBA1A gene.

BACKGROUND: Tubulinopathies include a wide spectrum of disorders ranging from abnormal ocular movement to severe brain malformations, and typically present as diffuse agyria or perisylvian pachygyria with microcephaly, agenesis of the corpus callosum, and cerebellar hypoplasia. They are caused by the dysfunction of tubulins encoded by tubulin-related genes, and the TUBA1A gene encoding alpha-1A tubulin is most frequently responsible for this clinical entity. Porencephaly is relatively rare among patients with the TUBA1A mutations. Mild case of tubulinopathy associated with porencephaly caused by a novel TUBA1A mutation. CASE REPORT: The patient, a 10-month-old girl, presented with gross motor delay at 4 months of age and convulsions at 7 months of age. Brain magnetic resonance imaging showed porencephaly, occipital polymicrogyria, hypoplasia of the corpus callosum, volume loss of the white matter, dysgenesis of anterior limbs of internal capsules, non-separative basal ganglia, cerebellar hypoplasia, and dysplastic brainstem. We identified a novel de novo heterozygous missense mutation in the TUBA1A gene, c.381C > A (p.Asp127Glu), by whole-exome sequencing. DISCUSSION: Microtubules composed of tubulins regulate not only neuronal migration but also cell division or axon guidance. Accordingly, tubulinopathy affects the cortical lamination, brain size, callosal formation, and white matter as seen in the present case. In contrast to the previously reported cases, the present case showed milder cortical dysgenesis with a rare manifestation of porencephaly. The genotype-phenotype correlation is still unclear, and this study expands the phenotypic range of tubulinopathy.

Fetal cytomegalovirus infection.

Cytomegalovirus (CMV) congenital infection affects 0.7% of live births worldwide and is the leading cause of congenital neurological handicap of infectious origin. However, systematic screening for this infection has not been implemented in pregnancy or at birth in any country. This apparent paradox had been justified by persisting gaps in the knowledge of this congenital infection: uncertain epidemiological data, difficulty in the diagnosis of maternal infection, absence of validated prenatal prognostic markers, unavailability of an efficient vaccine and scarcity of data available on the treatment. However, in the last decade, new data have emerged towards better management of this congenital infection, including solid epidemiological data, good evidence for the accuracy of diagnosis of maternal CMV infection and good evidence for the feasibility of predicting the outcome of fetal infection by a combination of fetal imaging and fetal laboratory parameters. There is also some evidence that valaciclovir treatment of mothers carrying an infected fetus is feasible, safe and might be effective. This review provides an update on the evidence for diagnosis, prognosis and treatment of congenital infection in the antenatal period. These suggest a benefit to a proactive approach for prenatal congenital infections.

Evaluation of long-term neurodevelopment in twin-twin transfusion syndrome after laser therapy.

OBJECTIVE: The primary objective of our study was to evaluate the long-term neurodevelopment outcome after laser surgery for twin-twin transfusion syndrome (TTTS). The secondary objective was to identify perinatal prognostic factors associated with neurodevelopmental impairment. METHOD: This was a single-center cohort prospective study carried out in pregnancies complicated by TTTS and treated by laser. Neurodevleopmental assesment included the administration of Ages and Stages Questionnaires® (ASQ), for the infants between 2 and 5 years of age. RESULTS: A total of 187 patients underwent a laser for TTTS between 2004 and 2013. Significant brain lesions were detected in eight (2.9%) cases by ultrasound and/or magnetic resonance imaging including intraventricular hemorrhage, periventricular leukomalacia, and porencephaly. Questionnaires were administered to 126 children (50.4%) at 24 months or older at the moment of testing. There were 13.5% of those infants who had an abnormal ASQ (established as one area or more scoring < 2 SD) at 3.6 years ±1.3 follow-up. There was a higher rate of abnormal ASQ among the infants with a birth weight below the fifth percentile (p = 0.036). CONCLUSION: Twin-twin transfusion syndrome is associated with a risk of abnormal neurological development, even in case of laser surgery. Further studies are necessary to identify the risk factors for neurological impairment. © 2016 John Wiley & Sons, Ltd.