In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)_n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)_n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8–15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.

Mutations in the gene coding for the skeletal muscle Cl⁻ channel (CLCN1) lead to dominant or recessive myotonia. Here, we identified and characterized CLCN1 mutations in Costa Rican patients, who had been clinically diagnosed with myotonic dystrophy type 1 but who were negative for DM1 mutations. CLCN1 mutations c.501C>G, p.F167L and c.1235A>C, p.Q412P appeared to have recessive inheritance but patients had atypical clinical phenotypes; c.313C>T, p.R105C was found in combination with c.501C>G, p.F167L in an apparently recessive family and the c.461A>G, p.Q154R variant was associated with a less clear clinical picture. In Xenopus oocytes, none of the mutations exhibited alterations of fast or slow gating parameters or single channel conductance, and mutations p.R105C, p.Q154R, and p.F167L were indistinguishable from wild‐type (WT). p.Q412P displayed a dramatically reduced current density, surface expression and exerted no dominant negative effect in the context of the homodimeric channel. Fluorescently tagged constructs revealed that p.Q412P is expressed inefficiently. Our study confirms p.F167L and p.R105C as myotonia mutations in the Costa Rican population, whereas p.Q154R may be a benign variant. p.Q412P most likely induces a severe folding defect, explaining the lack of dominance in patients and expression systems, but has WT properties once expressed in the plasma membrane.

Introducción: la obesidad es un rasgo multifactorial determinado por la interacción de factores biológicos, ambientales, psicosociales y político-socioeconómicos. Propósito: el objetivo de esta revisión descriptiva-exploratoria es discutir el papel del consumo de alimentos altamente procesados y de alta palatabilidad (APAP) en la epidemia de la obesidad, así como presentar algunas propuestas para disminuir su ingesta. Argumentos para la discusión: los APAP se caracterizan por ser energéticamente densos, ricos en grasas y azúcares. En su formulación se utiliza una gran cantidad de aditivos industriales para potenciar su sabor, vida útil y la estabilidad de sus componentes. Suelen contener sustancias químicas conocidas como disruptores endocrinos (EDC) que se transfieren de los empaques al alimento, como el bisfenol A y los ftalatos, y afectan distintas vías de señalización hormonal, promoviendo alteraciones en el metabolismo del tejido adiposo y otros sistemas endocrinos. El sobreconsumo de APAP induce a cambios neuroplásticos en el sistema de recompensa y esto aumenta, a la vez, el número de porciones, con la subsecuente acumulación de grasa corporal; además, dicho abuso causa desbalances en la composición del microbioma intestinal (disbiosis) asociados al desarrollo de obesidad. Conclusiones: el sobreconsumo de APAP incrementa el riesgo de obesidad y enfermedades crónicas no transmisibles, máxime si se inicia a edades tempranas. Para contrarrestar esta problemática, se plantea cambiar la estructura de la canasta básica, regular la venta dentro y alrededor de centros educativos, crear mayores impuestos y fortalecer la investigación en obesidad, APAP y EDC.