Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal-recessive dilated cardiomyopathy

Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1–4]), 40 -phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 40 -phosphopantothenoylcysteine to 40 -phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare, severe inborn error of metabolism due to pathogenic variants of PPCDCConsejería de Educaci on, Juventud y Deporte, Comunidad de Madrid, Grant/Award Number: B2017/BMD3721; Instituto de Salud Carlos III, Grant/Award Number: PI19/01155; Ministerio de Economía, Industria y Competitividad, Grant/Award Number: BFU2017-82574-

Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal-recessive dilated cardiomyopathy

12 páginas, 6 figurasCoenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1-4]), 4'-phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4'-phosphopantothenoylcysteine to 4'-phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare, severe inborn error of metabolism due to pathogenic variants of PPCDC.This work was funded by the Instituto de Salud Carlos (ISCIII), the European Regional Development Fund [PI19/01155], the Ministerio de Economía, Industria y Competitividad, Spain (BFU2017-82574-P), and the Consejería de Educacion, Juventud y Deporte, Comunidad de Madrid [B2017/BMD3721].Peer reviewe

Megaproyectos urbanos y productivos. Impactos socio-territoriales

El desarrollo de megaproyectos productivos trae consigo oportunidades para el crecimiento económico, la generación de empleos y el desarrollo regional. No obstante, en la actualidad, los grandes temas como la expansión urbana, el desarrollo industrial, las cementeras, la minería, el uso intensivo del agua y demás recursos naturales, preocupan a las comunidades por los impactos generados y porque en lo general, no consideran la racionalidad y responsabilidad ambiental y social hacia el entorno. En este contexto son diversos los estudios científicos que, en el marco de la política de económica imperante, intentan posicionarse como alternativas a proyectos económicos que confrontan los intereses particulares y comunitarios y que afectan la salud humana y ambiental. Megaproyectos urbanos y productivos. Impactos socio-territoriales, reúne veinticinco textos académicos sobre las afectaciones que éstos emprendimientos tienen para la sociedad y el entorno. Los temas expuestos recogen experiencias en el desarrollo urbano, industrial, turístico, portuario y aeroportuario, entre otros. Así mismo se retoman temas como la ética, la dialéctica, la política y la economía y su relación en el emprendimiento de megaproyectos. La búsqueda de esquemas productivos racionales y responsables con el entorno, que reivindiquen el derecho de las comunidades a un medio ambiente sano, a la preservación del territorio y sus recursos y de las formas de vida tradicionales, son los referentes para la realización del presente libro. Como elemento central se concibe el territorio como contenedor de identidad y vida, siendo preocupación y tema de estudio de la comunidad académica, las organizaciones de la sociedad civil y las redes de activistas organizados.UAEM, CONACyT, se

Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort

Objectives: This study aimed to assess the real use of cefazolin for methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) in the Spanish National Endocarditis Database (GAMES) and to compare it with antistaphylococcal penicillin (ASP). Methods: Prospective cohort study with retrospective analysis of a cohort of MSSA IE treated with cloxacillin and/or cefazolin. Outcomes assessed were relapse; intra-hospital, overall, and endocarditis-related mortality; and adverse events. Risk of renal toxicity with each treatment was evaluated separately. Results: We included 631 IE episodes caused by MSSA treated with cloxacillin and/or cefazolin. Antibiotic treatment was cloxacillin, cefazolin, or both in 537 (85%), 57 (9%), and 37 (6%) episodes, respectively. Patients treated with cefazolin had significantly higher rates of comorbidities (median Charlson Index 7, P <0.01) and previous renal failure (57.9%, P <0.01). Patients treated with cloxacillin presented higher rates of septic shock (25%, P = 0.033) and new-onset or worsening renal failure (47.3%, P = 0.024) with significantly higher rates of in-hospital mortality (38.5%, P = 0.017). One-year IE-related mortality and rate of relapses were similar between treatment groups. None of the treatments were identified as risk or protective factors. Conclusion: Our results suggest that cefazolin is a valuable option for the treatment of MSSA IE, without differences in 1-year mortality or relapses compared with cloxacillin, and might be considered equally effective