Phox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models.

Loss- and gain-of-function variants in the gene encoding KCNQ2 channels are a common cause of developmental and epileptic encephalopathy, a condition characterized by seizures, developmental delays, breathing problems, and early mortality. To understand how KCNQ2 dysfunction impacts behavior in a mouse model, we focus on the control of breathing by neurons expressing the transcription factor Phox2b which includes respiratory neurons in the ventral parafacial region. We find Phox2b-expressing ventral parafacial neurons express Kcnq2 in the absence of other Kcnq isoforms, thus clarifying why disruption of Kcnq2 but not other channel isoforms results in breathing problems. We also find that Kcnq2 deletion or expression of a recurrent gain-of-function variant R201C in Phox2b-expressing neurons increases baseline breathing or decreases the central chemoreflex, respectively, in mice during the light/inactive state. These results uncover mechanisms underlying breathing abnormalities in KCNQ2 encephalopathy and highlight an unappreciated vulnerability of Phox2b-expressing ventral parafacial neurons to KCNQ2 pathogenic variants.

Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology.

Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE.

Impaired white matter development in extremely low-birth-weight infants with previous brain hemorrhage.

BACKGROUND AND PURPOSE: Brain hemorrhage is common in premature infants. The purpose of the study is to evaluate white matter development in extremely low-birth-weight infants with or without previous brain hemorrhage. MATERIALS AND METHODS: Thirty-three extremely low-birth-weight infants were prospectively enrolled and included in this institutional review board-approved study. Another 10 healthy term infants were included as controls. The medical records of the extremely low-birth-weight infants were reviewed for sonography diagnosis of intraventricular hemorrhage. All infants had an MR imaging examination at term-equivalent age for detection of previous hemorrhage, and their white matter was scored and compared among different groups. DTI measured fractional anisotropy values were also compared voxelwise by tract-based spatial statistics. RESULTS: Compared with controls, the white matter score was not significantly different in extremely low-birth-weight infants without blood deposition on MR imaging (P = .17), but was significantly worse in extremely low-birth-weight infants with blood deposition on MR imaging but no intraventricular hemorrhage diagnosis by sonography (P = .02), in extremely low-birth-weight infants with grade 1 or 2 intraventricular hemorrhage on sonography (P = .003), and in extremely low-birth-weight infants with grade 3 or 4 intraventricular hemorrhage on sonography (P = .0001). Extremely low-birth-weight infants without blood deposition on MR imaging did not show any white matter regions with significantly lower fractional anisotropy values than controls. Extremely low-birth-weight infants with blood deposition on MR imaging, but no intraventricular hemorrhage diagnosis, did show white matter regions with significantly lower fractional anisotropy values, and extremely low-birth-weight infants with intraventricular hemorrhage diagnosis had widespread white matter regions with lower fractional anisotropy values. CONCLUSIONS: Previous brain hemorrhage is associated with abnormal white matter in extremely low-birth-weight infants at term-equivalent age, and sonography is not sensitive to minor hemorrhages that are sufficient to cause white matter injury.