A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

SCN5A encodes the alpha-subunit (Na(v)1.5) of the principle Na(+) channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Na(v)1.5 channel. Pharmacological targeting of mutation-altered Na(+) channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+) channel blockers flecainide and mexiletine. Our goal was to determine the Na(+) channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+) channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+) channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+) channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young

Factors controlling soil development in sand dunes: evidence from a coastal dune soil cronosequence

Aerial photographs, maps and optically stimulated luminescence dates were combined with existing soil data to construct high resolution chronosequences of soil development over 140 years at a temperate Atlantic UK dune system. Since soil formation had progressed for varying duration under different climate and nitrogen deposition regimes, it was possible to infer their relative influence on soil development compared with location-specific variables such as soil pH, slope and distance to the sea. Results suggest that soil development followed a sigmoid curve. Soil development was faster in wet than in dry dune habitats. In dry dunes, rates were greater than in the literature: they increased with increasing temperature and nitrogen deposition and decreased with increasing summer gales. The combination explained 62% of the variation. Co-correlation meant that effects of nitrogen deposition could not be differentiated from temperature. In wet dune habitats rates increased with temperature and decreased with gales. The combination explained only 23% of the variation; surprisingly, rainfall was not significant. Effects of location-specific variables were not significant in either habitat type. Nitrogen accumulation was faster in wet than dry dune habitats, averaging 43 kg N ha−1 per year overall. Nitrogen accumulation greatly exceeded inputs from atmospheric deposition, suggesting rates of input for biological N fixation are 10–60 kg N ha−1 per year. Recent climate and/or nitrogen deposition regimes may have accelerated soil development compared with past rates. These data suggest the importance of changing climate on soil development rates and highlight the contribution of biological N fixation in early successional systems

Role of congenital long-QT syndrome in unexplained sudden infant death: proposal for an electrocardiographic screening in relatives.

International audienceINTRODUCTION: Congenital long-QT syndrome (LQTS) is a sporadic or familial inherited arrhythmia. It can lead to sudden death by ventricular fibrillation which occurs at any age but particularly during infancy. Recent studies of postmortem molecular analysis in infants who died of unexplained sudden infant death syndrome (SIDS) showed abnormal mutations to LQTS in 10% to 12%. Current methods of etiologic investigation of sudden infant death syndrome do not allow the diagnosis of LQTS. A targeted anamnesis together with systematic electrocardiograms of first- and second-degree relatives could be an efficient LQTS diagnostic tool. Therefore, we propose to include them in screening procedures for SIDS etiologies. CONCLUSION: LQTS accounts for a significant number of unexplained SIDS. We suggest adding a systematic familial electrocardiographic screening to the current etiologic investigations in order to track congenital LQTS in relatives