ABSTRACT
Presynaptic congenital myasthenic syndromes (CMS) are a group of genetic disorders affecting the presynaptic side of the neuromuscular junctions (NMJ). They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft. Other proteins involved in presynaptic endplate development and maintenance can also be impaired.Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis. However, milder phenotypes with proximal muscle weakness and good response to treatment have been described. Finally, many presynaptic genes are expressed in the brain, justifying the presence of additional central nervous system symptoms.Several animal models have been developed to study CMS, providing the opportunity to identify disease mechanisms and test treatment options. In this review, we describe presynaptic CMS phenotypes with a focus on in vivo models, to better understand CMS pathophysiology and define new causative genes.
Subject(s)
Arthrogryposis , Myasthenic Syndromes, Congenital , Animals , Neuromuscular Junction/metabolism , Muscle Weakness , PhenotypeABSTRACT
Pannexin 1 (PANX1) is expressed in many tissue types including tissues of neural origin. Neuroblastoma (NB) is a neural crest-derived malignancy mainly occurring in children. The majority of NB patients present with high-risk disease for which current therapies are ineffective. Here, we show that while PANX1 is expressed in NB of all stages, high PANX1 expression in high-risk NB is associated with a reduced survival probability. PANX1 channel inhibition using probenecid (PBN) or carbenoxolone (CBX) reduced the proliferation of our panel of high-risk NB cell lines. We show that expression of the Y10F PANX1 mutant, which cannot be phosphorylated on tyrosine 10 and acts in a dominant-negative manner, curtailed NB cell proliferation. Furthermore, PBN and CBX treatment halted the growth of NB spheroids and in some cases triggered the regression of established NB spheroids. Finally, both drugs reduced the progression of high-risk NB in vivo. Together our data indicate that PANX1 channels regulate human NB malignant properties and that the use of PBN or CBX may provide a new therapeutic approach for high-risk NB.
ABSTRACT
STUDY OBJECTIVES: Despite the importance of treating sleep-disordered breathing, positive airway pressure adherence rates in children are low. Identifying readily available predictors of nonadherence would enable the development of targeted interventions and supports, but literature is limited. Our objective was to identify baseline clinical predictors of 6-month positive airway pressure therapy nonadherence in children with SDB through a retrospective cohort study. METHODS: This study evaluated children (ages 8-17 years) prescribed positive airway pressure therapy for sleep-disordered breathing between 2011 and 2017 at a single pediatric tertiary hospital. The primary outcome was nonadherence at 6 months, measured using both machine downloads and self-report. Candidate baseline predictors included demographics, comorbidities, and sleep-disordered breathing characteristics. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a modified Poisson regression. Missing data were imputed prior to analysis. RESULTS: The study included 104 children. The independent predictors most strongly associated with greater nonadherence were older age (RR = 1.08 for a 1-year increase; 95% CI, 1.00-1.16) and higher oxygen saturation nadir (RR = 1.03 for a 1% increase; 95% CI, 1.00-1.05), whereas those most strongly associated with lower nonadherence were higher arousal index (RR = 0.97 for a 1 event/h increase; 95% CI, 0.95-1.00), developmental delay (RR = 0.58; 95% CI, 0.30-1.13), and asthma (RR = 0.72; 95% CI, 0.44-1.17). CONCLUSIONS: Overall, children who are older, have less-severe sleep-disordered breathing, or less-disrupted sleep at baseline are more likely to be nonadherent to positive airway pressure therapy and may benefit from additional supports to acclimatize to therapy. As clinical predictors were only weakly associated with nonadherence, nonclinical characteristics may play a larger role in predicting adherence.
