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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Arousal States, Symptoms, Behaviour, Sleep and Body Temperature

Autonomic arousal (or affective states, e.g. stress, anxiety), symptoms (e.g. fatigue, pain), sleep-disrupting behaviour (e.g. physical inactivity, electronic device use, TV watching, shift work) and medications are linked to impaired sleep and, in many cases, overweight/obesity. Further, in many cases, the phenomena are linked to an elevated BT, and in some cases, a high nocturnal BT, although there is a lack of specific research pertaining to nocturnal BT and the relationship between BT and chronic pain. A relative hyperthermia at night is known to interfere with sleep onset, possible via a phase-shift in the sleep-wake cycle. However, an elevated BT can additionally lead to activation of the inflammatory response system (e.g. cytokine secretion), which may represent another possible mechanism by which the aforementioned states, symptoms, disorders and behaviour can develop