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Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (β-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla., (© 2023. The Author(s).)

Background: Septo-optic dysplasia (SOD), once a variable triad of septum pellucidum defects (SPDs), optic nerve hypoplasia (ONH), and hypopituitarism, has had multiple findings added, with uncertain causes, definitions, and limits., Method: Literature review., Results: SOD is a complex vascular sequence with confounders., Conclusions: Proximal anterior cerebral artery trunk disruptions cause overlapping primary effects, giving ONH alone most often, and isolated SPD less. ONH disruptions can spread to pituitary, SPD disruptions to the cerebral cortex, causing schizencephaly and related anomalies. Pituitary defects are rare without ONH, and cortical findings are rare without SPD. Extensions are unidirectional, so isolated pituitary or cortical defects are separate from SOD. Micro- an- ophthalmia, a suggested ONH variant, is not part of SOD. Disruption by-products can affect development, causing cognitive and endocrine issues, and structural anomalies such as corpus callosum thinning, ventriculomegaly, and hippocampal and olfactory findings. Limbic extensions may also contribute to the same structural defects as by-products. Midline CNS developmental anomalies can act as disruptive foci, most likely through vascular variants, but have separate pathogenesis. Relative frequencies of specific pituitary hormone defects change as SOD rates increase. Increasing relative rates of midline CNS developmental defects and cortical anomalies are consistent with rising levels of exogenous exposures sensitizing to midline predispositions., (© 2022 Wiley Periodicals LLC.)

The recent finding that some patients with fetal akinesia deformation sequence (FADS) carry variants in the TUBB2B gene has prompted us to add to the existing literature a first description of two fetal FADS cases carrying TUBA1A variants. Hitherto, only isolated cortical malformations have been described with TUBA1A mutation, including microlissencephaly, lissencephaly, central pachygyria and polymicrogyria-like cortical dysplasia, generalized polymicrogyria cortical dysplasia, and/or the "simplified" gyral pattern. The neuropathology of our fetal cases shows several common features of tubulinopathies, in particular, the dysmorphism of the basal ganglia, as the most pathognomonic sign. The cortical ribbon anomalies were extremely severe and concordant with the complex cortical malformation. In conclusion, we broaden the phenotypic spectrum of TUBA1A variants, to include FADS., (© 2022 Wiley Periodicals LLC.)

Background: Increasing number of mutations responsible for vascular lesions, leading to ischemic or hemorrhagic stroke in young adults, has been identified in the recent years. It has been demonstrated in both mice and humans, that mutations in COL4A1 gene promote cerebral hemorrhages. In humans, both adults and children may be affected, and the spectrum has been broadened recently to neonates and fetuses., Methods: We present a cohort of eight COL4A1 mutated fetuses in which cerebral hemorrhages were detected by ultrasound leading to elective terminations of pregnancy., Results: Our neuropathological studies demonstrated a strikingly similar pathological pattern, dominated by supra- and infratentorial multifocal hemorrhagic lesions of various abundance and age in the vicinity of enlarged small vessels having a discontinuous wall. This was constantly associated with a spectrum of supratentorial post-ischemic damages of the grey and white matters. Morphometric studies of brain vessels confirmed vascular dilation and hypervascularization in both grey and white matters and severe attenuation of the smooth-muscle actin staining in the white matter., Conclusion: These observations add to the rare human neuropathological phenotype of COL4A1 mutations. Its recognition is mandatory to enhance the number of tested patients in the future, as well as the genetic counseling of parents.

Background: Neuronal ceroid lipofuscinoses (NCLs) form a clinically and genetically heterogeneous group of inherited neurodegenerative disorders that share common neuropathological features. Although they are the first cause of neurodegenerative disorders in children, their congenital forms are rarely documented. They are classically due to mutations in the CTSD gene (the CLN10 disease). Affected newborns usually present severe microcephaly, seizures and respiratory failure leading to death within the first postnatal days or weeks., Cases: We report on two siblings, in which exome sequencing identified a novel homozygous CTSD variant. The first sib presented at birth with seizures, rapidly progressive postnatal microcephaly and visual deficiency related to retinal dysfunction. Progressive neurological deterioration leads to death at the age of 24 months. Cathepsin D activity was reduced in the cultured fibroblasts of this patient. The second sib, a fetus of 36 weeks of gestation, was delivered after pregnancy termination for brain abnormalities (in accordance with French Legislation) suggesting a recurrence of the disease. Fetal postmortem examination disclosed neuropathological features consistent with NCL., Conclusions: Congenital NCL related to CTSD mutations is a neuronal storage disorder that produces in the developing brain diffuse neurodegeneration and white matter atrophy resulting in a progressive and rapidly lethal microcephaly., (© 2021 Wiley Periodicals LLC.)