A de novo heterozygous missense BSCL2 variant in 2 siblings with intractable developmental and epileptic encephalopathy

Purpose: We present the case of 2 siblings with profound refractory epilepsy and neurological regression that began at the ages of 3 and 6 months. Diagnosis remained elusive despite extensive metabolic and genetic workups, including use of a targeted next-generation sequencing panel for epilepsy genes. Methods: Whole-exome sequencing was performed for the 2 siblings and their unaffected parents, in addition to fibroblast cell culture, RNA extraction and reverse-transcription, and cDNA PCR. Brain tissue from one of the siblings was collected post-mortem for neuropathological examination, including histology and immunohistochemistry. Results: Ade novo nucleotide change (c.566 T > A; p.(Met189Lys)) in exon 4 of the BSCL2 gene was detected in the 2 siblings, and confirmed by Sanger sequencing. This variant was absent in the parents and in a third, unaffected sibling. Conclusion: Given thede novo nature of the variant, its absence from public and in-house databases, our in silico pathogenicity predictions, and co-segregation of the variant with the disease phenotype, we believe that this novel variant is associated with the epileptic encephalopathy phenotype of the 2 siblings. Our findings provide the first evidence of an association between a heterozygous BSCL2 variant and developmental and early infantile epileptic encephalopathy. Further functional studies will be needed to elucidate the pathophysiological mechanisms underlying this new BSCL2-associated phenotype.This research was partially funded by the Consellería de Industria, Xunta de Galicia (grant number ED341b 2017/19), and by Fundación Mutua Madrileña (Call 2015). S.S-I is a recipient of a Research Fellowship from the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

Normalization of circulating plasma levels of miRNAs in HIV-1/HCV co-infected patients following direct-acting antiviral-induced sustained virologic response

In a previous recent work, we recognized three plasma circulating microRNAs (miRNAs)-miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p-that correlate largely with liver fibrosis evolution in human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV) co-infected patients. Here, we investigated whether levels of these three circulating miRNAs can be associated to liver disease evolution in HIV-1/HCV co-infected patients which have achieved HCV sustained virologic response (SVR) 12 weeks after finishing treatment. Eighty-one chronic HIV-1/HCV co-infected patients were longitudinally recruited at baseline (T0) of DAA therapy and 12 weeks (T12) after finishing therapy. At T0 most of the study patients displayed transient elastography values linked to an advanced stage of liver fibrosis (F0-1 9%, F2 11%, F3 32%, F4 48%). Significant reductions in the levels of circulating miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p were detected at T12 in SVR patients, in the overall cohort (P < 0.0001, P < 0.0001, and P = 0.0008, respectively) and in patients with advanced (F3-4) liver fibrosis (p < 0.0001, p < 0.0001, and P = 0.0011, respectively). Of note, no significant reduction in the study miRNA levels was found at T12 in patients who did not achieve SVR (P = 0.8750, P = 0.1250, and P = 0.1260, respectively). HCV-cured patients, in contrast to non-responders, significantly reduced their liver stiffness after two years of achieving SVR (p < 0.0001). DAA-induced SVR is linked with a significant reduction in circulating levels of miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p. Our results indicate that miRNA plasma levels may be a useful biomarker of liver damage progression in HIV-1/HCV co-infected individuals that reach DAA-induced SVR

Reductive Hydrogenation of Sulfido-Bridged Tantalum Alkyl Complexes: A Mechanistic Insight

Hydrogenolysis of a series of alkyl sulfido-bridged tantalum(IV) dinuclear complexes [Ta(?5-C5Me5)R(?-S)]2 [R = Me, nBu (1), Et, CH2SiMe3, C3H5, Ph, CH2Ph (2), p-MeC6H4CH2 (3)] has led quantitatively to the Ta(III) tetrametallic sulfide cluster [Ta(?5-C5Me5)(?3-S)]4 (4) along with the corresponding alkane. Mechanistic information for the formation of the unique low-valent tetrametallic compound 4 was gathered by hydrogenation of the phenyl-substituted precursor [Ta(?5-C5Me5)Ph(?- S)]2, which proceeds through a stepwise hydrogenation process, disclosing the formation of the intermediate tetranuclear hydride sulfide [Ta2(?5-C5Me5)2(H)Ph(?-S)(?3-S)]2 (5). Extending our studies toward tantalum alkyl precursors containing functional groups susceptible to hydrogenation, such as the allyl-and benzylsubstituted compounds [Ta(?5-C5Me5)(?3-C3H5)(?-S)]2 and [Ta(?5-C5Me5)(CH2Ph)(?-S)]2 (2), enables alternative reaction pathways en route to the formation of 4. In the former case, the dimetallic system undergoes selective hydrogenation of the unsaturated allyl moiety, forming the asymmetric complex [{Ta(?5-C5Me5)(?3-C3H5)}(?-S)2{Ta(?5-C5Me5)(C3H7)}] (6) with only one propyl fragment. Species 2, in addition to the hydrogenation of one benzyl fragment and concomitant toluene release, also undergoes partial hydrogenation and dearomatization of the phenyl ring on the vicinal benzyl unity to give a ?5-cyclohexadienyl complex [Ta2(?5-C5Me5)2(?-CH2C6H6)(?-S)2] (7). The mechanistic implications of the latter hydrogenation process are discussed by means of DFT calculationsComunidad de MadridUniversidad de AlcaláPrograma Estímulo a la Investigación de Jóvenes Investigadore

Efficient muscle distribution reflects the positive influence of coenzyme Q10 Phytosome in healthy aging athletes after stressing exercise

Coenzyme Q10 (CoQ10) is an ubiquitously-distributed molecule with a key role in mitochondrial efficiency, involving protection against peroxidation induced by reactive oxygen species. In athletes during intense training and strenuous exercise, a reactive oxygen species overproduction occurs and can cause muscular stress and damage: a reduction of those undesired effects would be of benefit. CoQ10 antioxidant properties are described in several clinical studies, but efficacy of CoQ10 supplementation in pre-senescent athletes has not yet been clearly demonstrated. A randomized, intervention-controlled, single-center clinical trial was performed in healthy aging (pre-senescent) runners undergoing exercise training in conditions of high environmental stress. One group used an innovative food-grade CoQ10 phytosome formulation (Ubiqsome) daily for 30 days, while the control group did not take supplementation. Phytosome technique applied to CoQ10 successfully increased CoQ10 bioavailability, as previously demonstrated. CoQ10 levels and oxidative with inflammatory markers were detected in both plasma and muscle. Data obtained highlighted that 500 mg of CoQ10 phytosome (corresponding to 100 mg CoQ10), administered once a day for 30 days significantly improved CoQ10 bioavailability in healthy volunteer aging runners (50-65 years) by increasing both plasmatic and muscular CoQ10 levels, with a reduction of inflammatory cytokines and Malonyl Dialdehyde levels suggesting a protective effect induced by supplementation. The original CoQ10 phytosome formulation results to be of benefit in increasing CoQ10 plasmatic and muscular levels when CoQ10 decrease occurred for oxidative stress conditions, aging or high training

Differences In Adipose Tissue And Lean Mass Distribution In Patients With Collagen Vi Related Myopathies Are Associated With Disease Severity And Physical Ability

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients

Copper Toxicity Associated With an ATP7A-Related Complex Phenotype

The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS), and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate.info:eu-repo/semantics/publishedVersio

Low levels of CIITA and high levels of SOCS1 predict COVID-19 disease severity in children and adults

It is unclear why COVID-19 ranges from asymptomatic to severe. When SARS-CoV-2 is detected, interferon (IFN) response is activated. When it is insufficient or delayed, it might lead to overproduction of cytokines and severe COVID-19. The aim was to compare cytokine and IFN patterns in children and adults with differing severity with SARS-CoV-2.It was a prospective, observational study, including 84 patients. Patients with moderate/severe disease had higher cytokines' values than patients with mild disease (p< 0.001).Two IFN genes were selected to build a decision tree for severity classification: SOCS1 (representative of the rest of the IFN genes) and CIITA (inverse correlation). Low values of CIITA and high values of SOCS1 indicated severe disease. This method correctly classified 33/38(86.8%) of children and 27/34 (79.4%) of adults. To conclude, patients with severe disease had an elevated cytokine pattern, which correlated with the IFN response, with low CIITA and high SOCS1 values.This study was supported by the projects PI18/00223, FI19/00208 and PI21/00211 to LA, integrated in the Plan Nacional de I + D + I and co-financed by the ISCIII– Subdirección General de Evaluación y Fomento de la Investigación Sanitaria – and the Fondo Europeo de Desarrollo Regional (FEDER), by Pla Estratègic de Recerca i Innovació en Salut (PERIS), Departament de Salut, Generalitat de Catalunya (SLT006/17/00199 to LA), and by CERCA Program/Generalitat de Catalunya. It was also partially funded by the Stavros Niarchos Foundation (SNF), Banco Santander, and other private donors of ‘‘KidsCorona platform’’ from Hospital Sant Joan de Déu.Peer ReviewedPostprint (published version