Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity.

Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dynamics simulations were performed on the Cx26 hemichannel embedded in a lipid bilayer. Exploring different initial conditions and calcium concentration, simulation reached ∼4 µs. Several analysis were carried out in order to reveal the calcium distribution and localization, such as electron density profiles, density maps and distance time evolution, which is directly associated to the interaction energy. Specific amino acid interactions with calcium and their stability were capture within this context. Few of these sites such as, GLU42, GLU47, GLY45 and ASP50, were already suggested in the literature. Besides, we identified novel calcium biding sites: ASP2, ASP117, ASP159, GLU114, GLU119, GLU120 and VAL226. To the best of our knowledge, this is the first time that these sites are reported within this context. Furthermore, since various pathologies involving the Cx26 hemichannel are associated with pathogenic variants in the corresponding CJB2 gene, using ClinVar, we were able to spatially associate the 3D positions of the identified calcium binding sites within the framework of this work with reported pathogenic variants in the CJB2 gene. This study presents a first step on finding associations between molecular features and pathological variants of the Cx26 hemichannel.

Estudo de 100 pacientes com clínica sugestiva de hipoglicemia e manifestaçöes de vertigem, surdez e zumbido / Study of 100 patients with suggestive clinics of hypoglycemia and manifestations of vertigo, deafness and tinnitus

O estudo avaliou a sensibilidade da história clínica para detectar alterações metabólicas em pacientes com hipoacusia e/ou zumbido e/ou vertigem associados à clínica sugestiva de hipoglicemia. Para tanto, 100 pacientes com este quadro foram submetidos a teste de tolerância à glicose de 5h com dosagem simultânea de insulina (hipoglicemia = glicose < ou = 55 mg/dL em qualquer momento da curva glicêmica). Curvas glicêmicas alteradas foram observadas em 59 pacientes (44 hipoglicêmicas). A hipoglicemia foi detectada apenas após a terceira hora do exame em 38 pacientes. As curvas insulinêmicas foram compatíveis com hiperinsulinismo em 73 pacientes. Apenas quatro pacientes apresentaram ambas as curvas dentro da normalidade. O valor preditivo positivo para detecção de anormalidades no metabolismo glicídico pela história clínica foi de 96 por cento. Este fato sugere a implantação de um teste terapêutico, com dieta específica, como parte da avaliação de pacientes com clínica sugestiva de hipoglicemia e manifestações de vertigem, surdez e zumbido.

Hipoacusias Metabólicas / Metabolic Hypoacusia

En el presente artículo el autor muestra la asociación entre alteraciones metabólicas e Hipoacusia. Muestra las diferentes opciones que hay para llegar a la hipoacusia por alteraciones del medio interno. Se mencionan las alteraciones del metabolismo hidroelectrolítico así como la de los líquidos del oído interno causantes de Hipoacusia. También se describe las alteraciones del calcio, fósforo y magnesio; así como alteraciones de los aminoácidos que conllevan a pérdidas de audición de tipo perceptivo.

This paper reviews the author ´s experience in cases o hypoacusia related to metabolic alterations. The author discusses the relationship between internal milieu and hypoacusia. Hydoelectrolytic metabolism disorders and disorders of liquid milieu in the inner aer are discussed as causes of hypoacusia. Calcium, phosphorus and magnesium disorders as well as aminoacid alterations as causes of hypoacusia are also discussed.

Mitochondrial electron transport chain defect presenting as hypoglycemia.

A profoundly deaf female infant was found to have hypoglycemia and lactic acidemia after an episode of decreased oral intake and vomiting. Electron transport chain (ETC) enzyme studies revealed a combination defect of complexes I, III, and IV in liver but not in skeletal muscle. This case highlights the fact that defects of the ETC are clinically highly heterogeneous and should be considered with hypoglycemia and lactic acidosis in the absence of a glycogen storage disorder. Moreover, ETC defects can occur with a biochemical profile suggestive of a fatty acid oxidation disorder.