There have been no published reports of central respiratory control abnormalities in pediatric patients with UNC80 or KCNJ11 mutations which cause neurologic channelopathies. We describe an 8-year-old male with a pathogenic UNC80 mutation, intellectual disability, hypotonia and epilepsy with severe central sleep apnea (213.5 events/h) on polysomnography (PSG). We also describe a 20-month-old female with a KCNJ11 mutation, neonatal diabetes and developmental delay who had severe central sleep apnea (131.1 events/h). Both patients had irregular respiratory patterns during sleep and wakefulness and were placed on empiric bilevel positive airway pressure therapy, which was well tolerated with resolution of abnormal respiratory control and hypercapnia. Patients with UNC80 and KCNJ11 gene mutations may have abnormal respiratory rhythm during sleep and wakefulness, mirroring animal models. We recommend routine PSG tests and further investigation into the respiratory control of patients with pediatric channelopathies involved in chemoreceptor function or central integration of respiratory control.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.