Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connections between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5000/8000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8-year-old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case under study follows a molecular pattern which is HHT-like. Therefore, molecular- biological and cellular-functional analyses have been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial-to-mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases

Endothelial to mesenchymal transition in an HHT-like pediatric case of multiple pulmonary arteriovenous malformations

15 p.-6 fig.-1 tab.Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connection between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5,000/8,000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao Criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8 years old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case of study follows a molecular pattern HHT-like. Therefore, molecular biology and cellular functional analysis has been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial to mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.This research was funded by MICINN (Ministry of Science and Innovation of Spain), grant number PID2020-115371RB-I00.N

Molecular and Cellular Characterization of Primary Endothelial Cells from a Familial Cavernomatosis Patient

Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this disease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression profiles of these cells were analyzed and compared to primary ECs from a healthy donor. The mutation of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased expression of genes involved in intercellular junction formation, angiogenesis, and vascular homeostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and somewhat predisposed to vascular damage

Mutation in Chek2 triggers von Hippel-Lindau hemangioblastoma growth

Purpose: Von Hippel-Lindau (VHL) is a rare inherited disease mainly characterized by the growth of tumours, predominantly hemangioblastomas (Hbs) in the CNS and retina, and renal carcinomas. The natural history of VHL disease is variable, differing in the age of onset and its penetrance, even among relatives. Unfortunately, sometimes VHL shows more severe than average: the onset starts in adolescence, and surgeries are required almost every year. In these cases, the factor that triggers the appearance and growth of Hbs usually remains unknown, although additional mutations are suspected.Methods: We present the case of a VHL patient whose first surgery was at 13 years of age. Then, along his next 8 years, he has undergone 5 surgeries for resection of 10 CNS Hbs. To clarify this severe VHL condition, DNA from a CNS Hb and white blood cells (WBC) was sequenced using next-generation sequencing technology.Results: Massive DNA sequencing of the WBC (germ line) revealed a pathogenic mutation in CHEK2 and the complete loss of a VHL allele (both tumour suppressors). Moreover, in the tumour sample, several mutations, in BRAF1 and PTPN11 were found. Familiar segregation studies showed that CHEK2 mutation was in the maternal lineage, while VHL was inherited by paternal lineage.Conclusions: Finally, clinical history correlated to the different genotypes in the family, concluding that the severity of these VHL manifestations are due to both, VHL-and-CHEK2 mutations. This case report aims to notice the importance of deeper genetic analyses, in inherited rare diseases, to uncover non-expected mutations.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was funded by the Ministry of Science and Innovation of Spain (grant number PID2020-115371RB-I00).Peer reviewe

A High Adherence to Six Food Targets of the Mediterranean Diet in the Late First Trimester is Associated with a Reduction in the Risk of Materno-Foetal Outcomes: The St. Carlos Gestational Diabetes Mellitus Prevention Study

A prenatal diet affects materno-foetal outcomes. This is a post hoc analysis of the St. Carlos gestational diabetes mellitus (GDM) Prevention Study. It aims to evaluate the effect of a late first-trimester (>12 gestational weeks) degree of adherence to a MedDiet pattern—based on six food targets—on a composite of materno-foetal outcomes (CMFCs). The CMFCs were defined as having emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age, and/or small-for-gestational-age. A total of 874 women were stratified into three groups according to late first-trimester compliance with six food targets: >12 servings/week of vegetables, >12 servings/week of fruits, <2 servings/week of juice, >3 servings/week of nuts, >6 days/week consumption of extra virgin olive oil (EVOO), and ≥40 mL/day of EVOO. High adherence was defined as complying with 5–6 targets; moderate adherence 2–4 targets; low adherence 0–1 targets. There was a linear association between high, moderate, and low adherence, and a lower risk of GDM, CMFCs, urinary tract infections (UTI), prematurity, and small-for-gestational-age (SGA) newborns (all p < 0.05). The odds ratios (95% CI) for GDM and CMFCs in women with a high adherence were 0.35((0.18–0.67), p = 0.002) and 0.23((0.11–0.48), p < 0.001), respectively. Late first-trimester high adherence to the predefined six food targets is associated with a reduction in the risk of GDM, CMFCs, UTI, prematurity, and SGA new-borns

A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region

An Early, Universal Mediterranean Diet-Based Intervention in Pregnancy Reduces Cardiovascular Risk Factors in the “Fourth Trimester”

An early antenatal dietary intervention could play an important role in the prevention of metabolic diseases postpartum. The aim of this study is to evaluate whether an early, specific dietary intervention reduces women’s cardiovascular risk in the “fourth trimester”. This prospective cohort study compares 1675 women from the standard-care group (ScG/n = 676), who received standard-care dietary guidelines, with the intervention group (IG/n = 999), who received Mediterranean diet (MedDiet)-based dietary guidelines, supplemented with extra-virgin olive oil and nuts. Cardiovascular risk was determined by the presence of metabolic syndrome (MetS) and insulin resistance syndrome (IrS) (HOMA-IR 3.5) at 12–14 weeks postpartum. MetS was less frequent in the IG (11.3 vs. 19.3%, p < 0.05). The intervention was associated with a reduction in the relative risk of having MetS: 0.74 (95% CI, 0.60–0.90), but not in the risk of IrS. When analyzing the presence of having one or more components of the MetS, the IG had significantly higher rates of having 0 components and lower rates of having ≥1 (p-trend = 0.029). An early MedDiet-based nutritional intervention in pregnancy is associated with reductions in postpartum rates of MetS

The Consumption of Food-Based Iodine in the Immediate Pre-Pregnancy Period in Madrid Is Insufficient. San Carlos and Pregnancy Cohort Study

A pre-gestational thyroid reserve of iodine is crucial to guarantee the increased demand for thyroid hormone production of early pregnancy. An iodine intake &ge;150 &micro;g/day is currently recommended. The objective of this study was to assess average pre-gestational food-based iodine consumption in pregnant women at their first prenatal visit (&lt;12 gestational weeks), and its association with adverse materno-fetal events (history of miscarriages, early fetal losses, Gestational Diabetes, prematurity, caesarean sections, and new-borns large/small for gestational age). Between 2015&ndash;2017, 2523 normoglycemic women out of 3026 eligible had data in the modified Diabetes Nutrition and Complication Trial (DNCT) questionnaire permitting assessment of pre-gestational food-based iodine consumption, and were included in this study. Daily food-based iodine intake was 123 &plusmn; 48 &micro;g, with 1922 (76.1%) not reaching 150 &micro;g/day. Attaining this amount was associated with consuming 8 weekly servings of vegetables (3.84; 3.16&ndash;4.65), 1 of shellfish (8.72; 6.96&ndash;10.93) and/or 2 daily dairy products (6.43; 5.27&ndash;7.86). Women who reached a pre-gestational intake &ge;150 &micro;g had lower rates of hypothyroxinemia (104 (17.3%)/384 (21.4%); p = 0.026), a lower miscarriage rate, and a decrease in the composite of materno-fetal adverse events (0.81; 0.67&ndash;0.98). Reaching the recommended iodine pre-pregnancy intake with foods could benefit the progression of pregnancy

Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials

A Mediterranean diet with additional extra virgin olive oil and pistachios reduces the incidence of gestational diabetes mellitus (GDM): A randomized controlled trial: The St. Carlos GDM prevention study

<div><p>Background</p><p>Gestational diabetes mellitus (GDM) prevalence is increasing and becoming a major public health concern. Whether a Mediterranean diet can help prevent GDM in unselected pregnant women has yet to be studied.</p><p>Methods</p><p>We conducted a prospective, randomized controlled trial to evaluate the incidence of GDM with two different dietary models. All consecutive normoglycemic (<92 mg/dL) pregnant women at 8–12 gestational weeks (GW) were assigned to Intervention Group (IG, n = 500): MedDiet supplemented with extra virgin olive oil (EVOO) and pistachios; or Control Group (CG, n = 500): standard diet with limited fat intake. Primary outcome was to assess the effect of the intervention on GDM incidence at 24–28 GW. Gestational weight gain (GWG), pregnancy-induced hypertension, caesarean section (CS), preterm delivery, perineal trauma, small and large for gestational age (SGA and LGA) and admissions to neonatal intensive care unit were also assessed. Analysis was by intention-to-treat.</p><p>Results</p><p>A total of 874 women completed the study (440/434, CG/IG). According to nutritional questionnaires and biomarker analysis, women in the IG had a good adherence to the intervention. 177/874 women were diagnosed with GDM, 103/440 (23.4%) in CG and 74/434(17.1%) in IG, p = 0.012. The crude relative risk (RR) for GDM was 0.73 (95% CI: 0.56–0.95; p = 0.020) IG vs CG and persisted after adjusted multivariable analysis, 0.75(95% CI: 0.57–0.98; p = 0.039). IG had also significantly reduced rates of insulin-treated GDM, prematurity, GWG at 24–28 and 36–38 GW, emergency CS, perineal trauma, and SGA and LGA newborns (all p<0.05).</p><p>Conclusions</p><p>An early nutritional intervention with a supplemented MedDiet reduces the incidence of GDM and improves several maternal and neonatal outcomes.</p></div