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BACKGROUND AND AIM: Recommendations on pregnancy, lactation, and contraception in women with Wilson disease are briefly stated in international guidelines but are not entirely homogeneous. Data regarding the management of these special events among patients with Wilson disease in Spain are lacking. We used the Wilson Registry platform of the Spanish Association for the Study of the Liver to question patients on their reproductive and gestational lives. METHODS: This was a multicentre ambispective study including adult women with Wilson disease in the Spanish Wilson Registry interviewed about their contraception, childbearing, pregnancy, and lactation experiences. Clinical and analytical data were extracted from the registry. RESULTS: The study included 92 women from 17 centres in Spain. Most (63%) reported having a previous pregnancy history. The rate of spontaneous miscarriages was 21.6%, mainly occurring in the first trimester and up to one third among undiagnosed patients. Most pregnant women received chelator therapy during pregnancy, but dose reduction was recommended in less than 10%. After delivery, artificial lactation predominated (60.3%) and its use was mainly based on physician's recommendations (68%). Up to 40% of the women included reported some concerns about their reproductive lives, mainly related to the potential drug toxicity to their children. Most of the patients considered the information given by specialists to be sufficient. CONCLUSION: Gestational management among women with Wilson disease in Spain was found to be highly heterogeneous and frequently different from what is described in international guidelines. Education on rare liver diseases should be a priority for scientific societies in order to homogenize patient follow-up and recommendations.
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PURPOSE: To determine the rate of genetic testing for familial hyperaldosteronism (FH) in the SPAIN-ALDO Registry and to describe the clinical characteristics of patients with FH. In addition, a literature review of reports of FH cases was performed. METHODS: A retrospective multicenter study of primary aldosteronism (PA) in patients followed in 35 Spanish tertiary hospitals (SPAIN-ALDO Registry). RESULTS: Twenty-five of the 855 patients (3%) with PA included in the registry underwent genetic testing for FH, with complete results available in only 24 patients. However, we found that there were 57 patients who met the criteria for performing a genetic study of PA. Only 8 out of these 57 patients were genetically tested (14.0%), while the reasons to perform a genetic study in the remaining 9 genetically studied cases were quite heterogeneous. A positive result for FH was found only in one case for FH type III (KCNJ5 pathogenic variant). A systematic review of the literature was performed and identified a total of 25 articles reporting 246 patients with FH type I; 12 articles reporting 72 patients with FH type II; 14 articles reporting 29 cases of FH type III and 3 articles reporting 12 patients with FH type IV. CONCLUSION: The genetic study of familial hyperaldosteronism is often scarce in real-world clinical practice, as 86% of patients with criteria to undergo genetic study were not evaluated in our cohort. Nevertheless, FH is an uncommon cause of PA, representing only 0.2% of cases in the SPAIN-ALDO Registry, although its prevalence may be as high as 4% among suspected cases might be studied.
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BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described. METHODS: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition. RESULTS: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery. CONCLUSIONS: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.
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Disección Aórtica , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Aneurisma/genética , Aneurisma/patología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Disección Aórtica/genética , Disección Aórtica/patología , ADN Metiltransferasa 3A , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , MutaciónRESUMEN
BACKGROUND: The term "post-COVID-19 condition" refers to the symptomatology that appears between four to twelve weeks after Covid-19 infection. These symptoms can persist for weeks or even months, significantly diminishing the quality of life for affected individuals. The primary objective of this study was to assess the effectiveness of pulmonary rehabilitation programs and/or respiratory muscle training on respiratory sequelae in patients with post-COVID condition. METHODS: The literature search was conducted in the following databases: PubMed, PEDro, Embase, Cochrane, Scopus, and Web of Science. Randomized clinical trials were included in which participants were aged 18 years or older. Articles were excluded if at least one of the therapies did not involve pulmonary rehabilitation or respiratory muscle training, if the participants were COVID positive, if studies lacked results, and finally, if interventions were conducted without supervision or at home. This review only encompasses supervised non-virtual interventions. This study adheres to the PRISMA statement and has been registered in the PROSPERO database (CRD42023433843). RESULTS: The outcomes obtained in the included studies are assessed across the following variables: Exercise capacity using the 6-minute walk test, Dyspnea, fatigue, Pulmonary function, Maximum inspiratory pressure, and Quality of life. CONCLUSION: Despite the absence of a specific treatment at present, it was evident from this review that a well-structured pulmonary rehabilitation program that incorporates both aerobic and muscular strength exercises along with techniques and inspiratory muscle exercises was the most effective form of treatment.
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Ejercicios Respiratorios , COVID-19 , Humanos , COVID-19/rehabilitación , Ejercicios Respiratorios/métodos , Resultado del Tratamiento , Músculos Respiratorios/fisiopatología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Tolerancia al Ejercicio/fisiología , Síndrome Post Agudo de COVID-19RESUMEN
BACKGROUND: Quantum Dots (QDs) are fluorescent nanoparticles with exceptional optical and optoelectronic properties, finding widespread utility in diverse industrial applications. Presently, chemically synthesized QDs are employed in solar cells, bioimaging, and various technological domains. However, many applications demand QDs with prolonged lifespans under conditions of high-energy radiation. Over the past decade, microbial biosynthesis of nanomaterials has emerged as a sustainable and cost-effective process. In this context, the utilization of extremophile microorganisms for synthesizing QDs with unique properties has recently been reported. RESULTS: In this study, UV-resistant bacteria were isolated from one of the most extreme environments in Antarctica, Union Glacier at the Ellsworth Mountains. Bacterial isolates, identified through 16 S sequencing, belong to the genera Rhodococcus, Pseudarthrobacter, and Arthrobacter. Notably, Rhodococcus sp. (EXRC-4 A-4), Pseudarthrobacter sp. (RC-2-3), and Arthrobacter sp. (EH-1B-1) tolerate UV-C radiation doses ≥ 120 J/m². Isolated UV-resistant bacteria biosynthesized CdS QDs with fluorescence intensities 4 to 8 times higher than those biosynthesized by E. coli, a mesophilic organism tolerating low doses of UV radiation. Transmission electron microscopy (TEM) analysis determined QD sizes ranging from 6 to 23 nm, and Fourier-transform infrared (FTIR) analysis demonstrated the presence of biomolecules. QDs produced by UV-resistant Antarctic bacteria exhibit high photostability after exposure to UV-B radiation, particularly in comparison to those biosynthesized by E. coli. Interestingly, red fluorescence-emitting QDs biosynthesized by Rhodococcus sp. (EXRC-4 A-4) and Arthrobacter sp. (EH-1B-1) increased their fluorescence emission after irradiation. Analysis of methylene blue degradation after exposure to irradiated QDs biosynthesized by UV-resistant bacteria, indicates that the QDs transfer their electrons to O2 for the formation of reactive oxygen species (ROS) at different levels. CONCLUSIONS: UV-resistant Antarctic bacteria represent a novel alternative for the sustainable generation of nanostructures with increased radiation tolerance-two characteristics favoring their potential application in technologies requiring continuous exposure to high-energy radiation.
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Compuestos de Cadmio , Puntos Cuánticos , Rhodococcus , Rayos Ultravioleta , Puntos Cuánticos/química , Regiones Antárticas , Compuestos de Cadmio/metabolismo , Compuestos de Cadmio/química , Rhodococcus/metabolismo , Rhodococcus/genética , Arthrobacter/metabolismo , Arthrobacter/genética , Sulfuros/metabolismo , Sulfuros/químicaRESUMEN
Abnormalities in auditory processing are believed to play a major role in autism and attention-deficit hyperactivity disorder (ADHD). Both conditions often co-occur in children, causing difficulties in deciding the most promising intervention. Event-related potentials (ERPs) have been investigated and are showing promise to act as potential biomarkers for both conditions. This study investigated mismatch negativity (MMN) using a passive listening task and P3b in an active auditory go/no-go discrimination task. Recordings were available from 103 children (24 females): 35 with ADHD, 27 autistic, 15 autistic children with co-occurring ADHD, and 26 neurotypical (NT) children. The age range considered was between 4 and 17 years, but varied between groups. The results revealed increases in the MMN and P3b amplitudes with age. Older children with ADHD exhibited smaller P3b amplitudes, while younger autistic children showed reduced MMN amplitudes in response to phoneme changes compared to their NT counterparts. Notably, children diagnosed with autism and ADHD did not follow this pattern; instead, they exhibited more similarities to NT children. The reduced amplitudes of phonetically elicited MMN in children with autism and reduced P3b in children with ADHD suggest that the two respective ERPs can act as potential biomarkers for each condition. However, optimisation and standardisation of the testing protocol, as well as longitudinal studies are required in order to translate these findings into clinical practice.
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Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms' severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.
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BACKGROUND: Cardiovascular comorbidity is a common companion of psoriasis and psoriatic arthritis (PsA). Recently, a significant link has been found between the HLA-Cw6 allele and a better cardiometabolic profile in these patients. We aimed to check this finding in our setting. METHODS: A cross-sectional observational study (n: 572 psoriasis patients, 30% with PsA) was conducted. Different study variables were collected in detail, as well as classic cardiometabolic risk factors. The distribution of the HLA-Cw6 allele and the IFIH1/MDA5 gene variants previously linked to disease risk were determined in the study cohort and stratified according to the cardiometabolic comorbidity. Linear and logistic regression models were constructed to analyze these associations. RESULTS: The study cohort included 309 men and 263 women, with a mean age of 46.7 years (SD 14.5) and a mean disease duration of 19.4 years (SD 14.8). We confirmed the known association between HLA-Cw6 and type I psoriasis (familial, severe, and early onset). Psoriasis severity (OR: 2.14), female sex (OR: 1.63), and the IFIH1/MDA5 rs1990760 TT genotype (OR: 1.62) were significantly related to PsA, while HLA-Cw6 was protective (OR: 0.65). HLA-Cw6 carriers showed a lower waist perimeter, lower BMI, and lower risk of both hypertension (OR: 0.52, p < 0.001) and diabetes (OR: 0.36, p < 0.001), but these findings were no longer apparent upon adjusting the regression models. No IFIH1/MDA5 gene variant was associated with any cardiometabolic risk factor. CONCLUSIONS: The influence of HLA-Cw6 on the cardiometabolic risk profile of psoriatic patients seems to be explained by other factors (age, sex, duration of the disease or arthritis) and not by this biomarker itself.
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Decreased body size is often cited as a major response to ocean warming. Available evidence, however, questions the actual emergence of shrinking trends and the prevalence of temperature-driven changes in size over alternative drivers. In marine fish, changes in food availability or fluctuations in abundance, including those due to size-selective fishing, provide compelling mechanisms to explain changes in body size. Here, based on three decades of scientific survey data (1990-2021), we report a decline in the average body size-length and weight-of anchovy, Engraulis encrasicolus L., in the Bay of Biscay. Shrinking was evident in all age classes, from juveniles to adults. Allometric adjustment indicated slightly more pronounced declines in weight than in total length, which is consistent with a change toward a slender body shape. Trends in adult weight were nonlinear, with rates accelerating to an average decline of up to 25% decade-1 during the last two decades. We found a strong association between higher anchovy abundance and reduced juvenile size. The effect of density dependence was less clear later in life, and temperature became the best predictor of declines in adult size. Theoretical analyses based on a strategic model further suggested that observed patterns are consistent with a simultaneous, opposing effect of rising temperatures on accelerating early growth and decreasing adult size as predicted by the temperature-size rule. Macroecological assessment of ecogeographical-Bergmann's and James'-rules in anchovy size suggested that the observed decline largely exceeds intraspecific variation and might be the result of selection. Limitations inherent in the observational nature of the study recommend caution and a continued assessment and exploration of alternative drivers. Additional evidence of a climate-driven regime shift in the region suggests, however, that shrinking anchovy sizes may signal a long-lasting change in the structure and functioning of the Bay of Biscay ecosystem.
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Bahías , Ecosistema , Animales , Clima , Temperatura , Tamaño Corporal/fisiología , Alimentos MarinosRESUMEN
Objectives: Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation: We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions: Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing.
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BACKGROUND AND AIMS: The fully-covered self-expanding metal stent (SEMS) has a role in the management of refractory acute variceal haemorrhage. The aim of this study was to evaluate its effectiveness and complications in real-world practice. PATIENTS AND METHODS: An observational, descriptive, multicenter study was carried out. Eight patients with clinically significant portal hypertension who underwent a SEMS were included. RESULTS: SEMS placement controlled acute bleeding in 7 patients with technical success. Stents were removed after a median of 8 days. Rescue transjugular intrahepatic portosystemic shunt was performed around 48 hours after SEMS placement. Four patients survived after successful SEMS removal. The most common adverse event was stent loop in 2 patients. CONCLUSIONS: In our experience, SEMS was highly effective in controlling acute refractory variceal bleeding. Bleeding-related mortality rate was probably due to impossibility of TIPS implantation. Stent loop was a common limiting factor.
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Frequency, association and impact measures are key concepts in clinical epidemiology; however, it has been found that a considerable proportion of health students and professionals have no knowledge of how to use or interpret them when reading a scientific paper or conducting research. This article aims to explain the main epidemiological measures, how they are used, derived and interpreted. They are approached from the perspective of each of the most frequently used types of primary quantitative research studies (randomized clinical trials, cohort studies, case-control estudies and cross-sectional studies) in order to provide the reader with the context in which they are used. Moreover, the process for calculating and interpreting each result in a real setting is explained using clinical examples for a better understanding of these concepts and in order to prevent their use from becoming just a mechanical or repetitive exercise.
Las medidas de frecuencia, asociación e impacto son conceptos fundamentales de la epidemiología clínica; sin embargo, se ha encontrado que una parte considerable de los estudiantes y de los profesionales en el área de la salud no sabe cómo usarlas ni cómo interpretarlas al leer un texto científico o al hacer una investigación. Este artículo busca explicar las principales medidas epidemiológicas, cuándo se usan, cómo se obtienen y cómo se interpretan. Se abordan desde cada tipo de estudios primarios más frecuentemente utilizados cuando se realizan investigaciones cuantitativas (ensayos clínicos aleatorizados, estudios de cohorte, casos y controles y estudios de corte transversal), con el fin de darle al lector el contexto en el cual se usan. Además, mediante ejemplos clínicos, se explica el proceso para calcular e interpretar cada resultado en un escenario real, con el fin de lograr una mayor comprensión de estos conceptos y de que su uso no sea un ejercicio mecánico o de repetición.
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WHO classified Candida albicans as one of the four critical priority fungi for public health worldwide in 2022. Conventional topical formulations commercially available for the treatment of cutaneous candidiasis are associated with low drug bioavailability at the infection site and the lack of a sustained therapeutic effect. The main objectives of this work were to develop new topical administration systems of clotrimazole (CLT) and study the influence of surfactants on the antifungal inhibitory efficacy. Therefore, the minimum concentration of CLT required to inhibit 50 % of growth (MIC50) was determined, obtaining a value of approximately 15 ng/mL. A non-ionic emulsion type 1, Beeler base cream, hydrogel and liposomes containing CLT were designed, prepared, characterized and their antifungal activity against C. albicans was tested. CLT loaded liposomes were small in size (102 nm), homogeneous (polydispersity index = 0.3) and uncharged (+0.07 mV), showing higher antifungal activity against C. albicans than that of the commercially available cream Canesten®. Furthermore, the antifungal activity of CLT was reduced in combination with surfactants such as Tween-80/Span-80 or Brij-S10. Sodium lauryl sulphate showed a fungicidal effect that disappeared when formulated as part of the Beeler base cream.
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Candidiasis , Clotrimazol , Clotrimazol/farmacología , Antifúngicos , Excipientes/farmacología , Liposomas/farmacología , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Candida albicans , Tensoactivos/farmacologíaRESUMEN
Objectives: The course of progressive liver damage after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) remains undetermined. We aimed to determine risk factors associated with the development of liver-related events (LREs) after SVR, focusing on the utility of non-invasive markers. Methods: An observational, retrospective study that included patients with advanced chronic liver disease (ACLD) caused by hepatitis C virus (HCV), who achieved SVR with DAAs between 2014 and 2017. Patients were followed-up until December 2020. LREs were defined as the development of portal hypertension decompensation and the occurrence of hepatocellular carcinoma (HCC). Serological markers of fibrosis were calculated before treatment and one and two years after SVR. Results: The study included 321 patients, with a median follow-up of 48 months. LREs occurred in 13.7% of patients (10% portal hypertension decompensation and 3.7% HCC). Child-Pugh [HR 4.13 (CI 95% 1.74; 9.81)], baseline FIB-4 [HR 1.12 (CI 95% 1.03; 1.21)], FIB-4 one year post-SVR [HR 1.31 (CI 95% 1.15; 1.48)] and FIB-4 two years post-SVR [HR 1.42 (CI 95% 1.23; 1.64)] were associated with portal hypertension decompensation. Older age, genotype 3, diabetes mellitus and FIB-4 before and after SVR were associated with the development of HCC. FIB-4 cut-off values one and two years post-SVR to predict portal hypertension decompensation were 2.03 and 2.21, respectively, and to predict HCC were 2.42 and 2.70, respectively. Conclusions: HCV patients with ACLD remain at risk of developing liver complications after having achieved SVR. FIB-4 evaluation before and after SVR may help to predict this risk, selecting patients who will benefit from surveillance.
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Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Hipertensión Portal , Neoplasias Hepáticas , Humanos , Hepacivirus/genética , Antivirales/uso terapéutico , Estudios Retrospectivos , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Hipertensión Portal/diagnóstico , Hipertensión Portal/complicaciones , Hipertensión Portal/tratamiento farmacológicoRESUMEN
En Chile, al 31 de diciembre del 2020 un 12,5% de los extranjeros eran de nacionalidad haitiana. Se desconoce el estado nutricional (EN) en embarazadas y lactantes; así como también la prevalencia de lactancia materna exclusiva (LME) de la población haitiana en Chile. Los objetivos de este trabajo fueron comparar: (i) el EN de embarazadas haitianas y chilenas, (ii) el EN de lactantes y (iii) la duración de la LME en hijos de madres haitianas y chilenas. Para esto se analizó la base de datos de la población haitiana y chilena atendidos entre los años 2016-2019 en el Centro de Salud Familiar (CESFAM) "Los Castaños" ubicado en la comuna de La Florida. En la etapa pre-gestacional, las embarazadas haitianas presentaron mayor prevalencia de bajo peso en comparación a embarazadas chilenas (p= 0,0003), mientras que al término del embarazo presentaron una mayor prevalencia de estado nutricional normal (p= 0,0001) y menor prevalencia de obesidad (p= 0,0001). Respecto al estado nutricional de los lactantes, sólo se observaron diferencias en el primer mes de vida, donde un 82% de los lactantes haitianos tenían un EN normopeso en comparación al 24% en los lactantes chilenos (p= 0,0001). No se observaron diferencias significativas en la prevalencia de LME hasta los 6 meses entre lactantes haitianos y chilenos (35,3% vs 30%, respectivamente). Es importante mencionar que ninguno de los dos grupos de lactantes cumplió con la meta establecida por la Organización Mundial de la Salud (OMS) que propone LME en los primeros seis meses de vida hasta al menos 50%. En conclusión, se evidencian diferencias en el EN de las embarazadas y lactantes de ambos países, mientras que la prevalencia de LME en ambos grupos fue similar.
In Chile, until December 31st, 2020, 12.5% of foreign residents were from Haiti. The nutritional status (NS) in pregnant women and infants is unknown; as well as the prevalence of exclusive breastfeeding (EBF) of the Haitian population residing in Chile. This study aimed to compare: (i) the NS of Haitian and Chilean pregnant women, (ii) the NS of infants, and (iii) the duration of EBF in children of Haitian and Chilean mothers. We analyzed the database of the Haitian and Chilean population attended between the years 2016-2019 at the Primary Care Health Center (CESFAM) "Los Castaños" located in the commune of La Florida. During the pregestational stage, the Haitian pregnant women had a higher prevalence of low weight compared to the Chilean pregnant women (p= 0,0003), whereas, at the end of the pregnancy, they had a higher prevalence of normal nutritional status (p= 0,0001) and a lower prevalence of obesity and a tendency at the end of pregnancy. Whereas at the end of the pregnancy, Chilean women had a higher prevalence of obesity. Regarding the nutritional status of the infants, differences were only observed in the first month of life, where 82% of Haitian infants had a normal weight compared to 24% of Chilean infants (p= 0.0001). No significant differences were observed in the prevalence of EBF up to 6 months between Haitian and Chilean infants (35.3% vs. 30%, respectively). It is important to mention that neither of the two groups of infants met the goal established by the World Health Organization (WHO) that proposes EBF for the first six months of life up to at least 50%. In conclusion, there are differences in the NE of pregnant and lactating women in both countries, while the prevalence of EBF in both groups was similar.
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Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
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Ceramidas , Esfingolípidos , Humanos , Ceramidas/metabolismo , Homeostasis , Mutación , Esfingolípidos/genética , Esfingolípidos/metabolismoRESUMEN
INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.
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Vestibulopatía Bilateral , Ataxia Cerebelosa , Enfermedades del Sistema Nervioso Periférico , Enfermedades Vestibulares , Humanos , Ataxia Cerebelosa/genética , Vestibulopatía Bilateral/complicaciones , Tos , Estudios Retrospectivos , Ataxia/complicaciones , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades Vestibulares/complicaciones , Síndrome , Trastornos de la Sensación/etiología , Reflejo Anormal/fisiologíaRESUMEN
BACKGROUND: Consanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders. METHODS: We retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders. RESULTS: The overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease. CONCLUSIONS: Our results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.
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Enfermedades Raras , Humanos , Consanguinidad , Secuenciación del Exoma , Estudios Retrospectivos , Genes Recesivos , Frecuencia de los Genes , Enfermedades Raras/genética , Tamización de Portadores GenéticosRESUMEN
Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals.