Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies

ICAR: endoscopic skull‐base surgery

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Moderate Traumatic Brain Injury: The Grey Zone of Neurotrauma

Moderate traumatic brain injury (MTBI) is poorly defined in the literature and the nomenclature “moderate” is misleading, because up to 15 % of such patients may die. MTBI is a heterogeneous entity that shares many aspects of its pathophysiology and management with severe traumatic brain injury. Many patients who ‘’talk and died’’ are MTBI. The role of neuroimaging is essential for the proper management of these patients. To analyze all aspects of the pathophysiology and management of MTBI, proposing a new way to categorize it considering the clinical picture and neuroimaging findings. We proposed a different approach to the group of patients with Glasgow Coma Scale (GCS) ranging from 9 through 13 and we discuss the rationale for this proposal. Patients with lower GCS scores (9–10), especially those with significant space-occupying lesions on the CT scan, should be managed following the guidelines for severe traumatic brain injury, with ICU observation, frequent serial computed tomography (CT) scanning and ICP monitoring. On the other hand, those with higher range GCS (11–13) can be managed more conservatively with serial neurological examination and CT scans. Given the available evidence, MTBI is an entity that needs reclassification. Large-scale and well-designed studies are urgently needed