Abstract
Warburg Micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by ocular, neurodevelopmental, and neuroendocrine abnormalities, most commonly caused by RAB3GAP1 variants. RAB3GAP1 encodes the catalytic subunit of the RAB3 GTPase-activating protein (RAB3GAP), which regulates vesicular release and membrane trafficking through Rab GTPase modulation. Although in vitro studies suggest that RAB3GAP1 dysfunction impairs autophagy, the neuropathology of WARBM in the developing Human brain remains undocumented. Here, we present the first detailed neuropathological and molecular analysis of Human WARBM, based on two related cases: a 3-month-old infant and a 23-week gestation fetus with biallelic RAB3GAP1 pathogenic variants. Histological examination of the fetal cerebral cortex and cerebellum revealed selective vulnerability, with cortical plate thinning, while Purkinje cells appeared preserved. Consistently, immunohistochemistry demonstrated widespread RAB3GAP1 expression in the frontal cortex of controls, but no detectable staining in WARBM, coinciding with disrupted neurogenic niches, including reduced SOX2-positive progenitor cells, disorganized radial glia, and increased caspase-3 expression. These changes were associated with fewer DCX- and CTIP2-positive neurons, which may reflect a combination of altered neurogenesis, impaired neuronal migration and increased cell death. However, no gross brain malformations were observed in the fetus, whereas cortical malformations were evident in the 3-month-old infant, pointing to a progressive neurodevelopmental disruption potentially driven by fetal corticogenesis defects. These changes were accompanied by marked dysregulation of autophagy markers, linking impaired autophagy to disrupted cortical development. In contrast, autophagy disruption in the fetal lens was already associated with bilateral cataracts. Studies in patient-derived skin fibroblasts using immunocytochemistry, western blotting, and electron microscopy confirmed autophagy defects and tissue-specific consequences to RAB3GAP1 disruption in WARBM. Collectively, our findings provide the first in-depth neuropathological characterization of WARBM, highlighting the essential role of RAB3GAP1 in early Human and support autophagy as a key pathogenic feature in this severe disorder. Supplementary Information: The online version contains supplementary material available at 10.1186/s40478-025-02204-8.