Limame et al. address the human-specific impact of microcephaly-associated mutations in the ASPM gene. Using human cortical organoids, they show that ASPM disruption causes early deviations of mitotic...

Circulating IgA-NS1 against Zika and dengue virus was validated as a sensitive, specific marker of postnatal orthoflavivirus exposure in infants, showing n

Limame et al. address the human-specific impact of microcephaly-associated mutations in the ASPM gene. Using human cortical organoids, they show that ASPM disruption causes early deviations of mitotic spindle orientation in ventricular progenitors, which leads to their precocious delamination and thereby to misspecification of outer radial glial cells.

Elevated preexisting maternal IgG-NS1 to DENV, rather than to ZIKV, has been associated with a reduced risk of microcephaly in congenital Zika syndrome (CZS), suggesting a protective role. While serological analysis of IgG and IgM has physiological limitations in infants, IgA-NS1 represents a marker of host exposure to orthoflavivirus, as it is not transferred transplacentally and reflects early active immune responses. This study evaluated circulating IgA-NS1 responses to ZIKV and DENV in mothers and infants prenatally exposed to ZIKV in southern Colombia, a dengue hyperendemic region.MethodsIn this multicentric study, we analyzed 164 mother-infant pairs with confirmed gestational ZIKV exposure during the Colombia 2015-2016 epidemic. Using optimized ELISAs with well-characterized clinical samples, we simultaneously assessed circulating IgA-NS1 responses against ZIKV and DENV1-4. Neurological outcomes were evaluated through pediatric follow-up to determine associations between IgA-NS1 and CZS-related microcephaly.ResultsIgA-NS1 ELISAs for ZIKV and DENV1-4 achieved sensitivity/specificity of 94%/97% and 86%/85%, respectively. DENV-exposed samples showed 26% cross-reactivity against ZIKV NS1. There was no evidence of placental transfer, and IgA-NS1 levels for ZIKV and DENV were comparable between mothers and infants with or without CZS-related microcephaly. However, circulating ZIKV and DENV IgA-NS1 increased postnatally and were higher in older children.ConclusionWhile circulating IgA-NS1 serves as a promising postnatal marker of orthoflavivirus exposure in infants due to its stability and lack of placental transfer, it does not appear to contribute to protection against severe CZS outcomes. These findings demonstrate that protective NS1-mediated immunity against microcephaly may be isotype-dependent.

BACKGROUND AND PURPOSE: Microcephaly with simplified gyral pattern (SGP) represents an often subtle subtype of malformation of cortical development that is commonly accompanied by epilepsy and neurode...

Researchers at VIB and KU Leuven have uncovered how mutations in the ASPM gene disrupt the development of neural stem cells that help the human brain grow. This disruption explains how these mutations cause microcephaly, a condition characterized by an abnormally small brain and head, often accompanied by intellectual disability. The discovery, published in Developmental Cell, also sheds light on how differences in brain development can make humans more susceptible to certain genetic conditions than other mammals.

Angelman syndrome is a severe neurodevelopmental disorder caused by loss of UBE3A, a gene encoding an E3 ubiquitin ligase (an enzyme that marks other…

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Zika virus envelope protein strongly inhibits early neural lineage differentiation by downregulating key genes in neurodevelopment, providing evidence for neurodevelopmental abnormalities such as microcephaly.