We present novel brain MRI findings in 2 children presenting with seizures due to TMCO1 mutation. Both children had absent olfactory bulbs and olfactory tracts and hippocampal malrotation. EEG demonstrated right temporal slow waves and intermittent focal slowing. One child had pontine hypoplasia, hypoplasia of bilateral optic nerves/chiasm, and an absent right cochlear nerve. In both children, there was increased mineralization in bilateral globi pallidi and bilateral substantia nigra on SWI sequence, possibly from excessive calcium. Ventriculomegaly and cavum septum pellucidum were also present in both children. Spine MRI revealed segmentation abnormalities including partial fusion of T2/T3 vertebral bodies and fusion of the posterior elements of T3-T5. Both children exhibited dysplastic and bifid ribs, demonstrating partial posterior fusion. Right renal agenesis was also noted in one child. TMCO1 mutation results in cerebro-facio-thoracic dysplasia (CFTD) due to abnormal calcium homeostasis. The transmembrane and coiled-coil domains 1 protein directs formation of endoplasmic reticulum calcium leak channels which facilitate calcium leak upon overload of the endoplasmic reticulum. Failure of calcium leak results in abnormal cell function resulting in delayed osteogenesis, reduced mitochondrial volume, reduced mitochondrial respiration, and decreased endoplasmic reticulum stress mediated apoptosis. These children have distinctive craniofacial dysmorphism, global developmental delay, and skeletal anomalies. Previous studies have demonstrated only mild ventriculomegaly, corpus callosum abnormalities, frontotemporal atrophy, and three cases of associated epilepsy. Olfactory bulb agenesis may be due to abnormal development of the cribriform plate of the ethmoid and failure of olfactory nerves to induce development of the olfactory bulb from the telencephalon. We demonstrate that TMCO1 may play a more extensive and previously undescribed role in neurodevelopment, specifically in the formation of the hippocampus, optic nerve, and pons.
SPR 2022 Annual Meeting & Postgraduate Course