RESUMEN
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.
Asunto(s)
Trastorno del Espectro Autista , Biomarcadores , Discapacidad Intelectual , Mitocondrias , Acidemia Propiónica , Humanos , Acidemia Propiónica/genética , Biomarcadores/sangre , Masculino , Femenino , Niño , Discapacidad Intelectual/genética , Mitocondrias/metabolismo , Preescolar , Adolescente , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/genética , Adulto , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Adulto Joven , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangre , CitratosRESUMEN
PURPOSE: To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. METHODS: Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. RESULTS: Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. CONCLUSION: Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.
Asunto(s)
Trasplante de Hígado , Acidemia Propiónica , Biomarcadores , Humanos , Laboratorios , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/genéticaRESUMEN
PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.
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Errores Innatos del Metabolismo de los Aminoácidos , Propionatos , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Biomarcadores , Pruebas Respiratorias , Humanos , Hígado , Ácido MetilmalónicoRESUMEN
PURPOSE: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.
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Acidemia Propiónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Creatinina/sangre , Estudios Transversales , Cistatina C/análisis , Cistatina C/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón , Lipocalina 2/análisis , Lipocalina 2/sangre , Masculino , Persona de Mediana Edad , Prevalencia , Acidemia Propiónica/epidemiología , Ácido Úrico/análisis , Ácido Úrico/sangreRESUMEN
Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.
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Argininosuccinatoliasa/genética , Aciduria Argininosuccínica/genética , Células Endoteliales/patología , Hipertensión/genética , Adolescente , Animales , Presión Sanguínea/genética , Células Cultivadas , Niño , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Neovascularización Patológica/genética , Óxido Nítrico/genética , Estrés Oxidativo/genética , Trastornos Innatos del Ciclo de la Urea/genéticaAsunto(s)
Mielofibrosis Primaria/genética , Proteínas de Transporte Vesicular/deficiencia , Anomalías Múltiples/genética , Trasplante de Médula Ósea , Niño , Consanguinidad , Resultado Fatal , Femenino , Disgenesia Gonadal 46 XY/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Linaje , Fenotipo , Mielofibrosis Primaria/congénito , Mielofibrosis Primaria/terapia , Síndrome , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologíaRESUMEN
Steroid 3-beta hydroxysteroid dehydrogenase type II (3ß-HSD2) deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). We report the genetic basis of 3ß-HSD2 deficiency arising from uniparental isodisomy (UPD) of chromosome 1. We describe a term undervirilized male whose newborn screen indicated borderline CAH. The patient presented on the 7th day of life in salt-wasting adrenal crisis. Steroid hormone testing revealed a complex pattern suggestive of 3ß-HSD deficiency. Chromosomal microarray and single nucleotide polymorphism analysis revealed complete UPD of chromosome 1. Sanger sequencing of HSD3B2 revealed a previously described missense mutation, c.424G>A (p.E142K) in homozygous state, thus confirming the diagnosis of 3ß-HSD2 deficiency. We provide evidence of the existence of an uncommon mechanism for HSD3B2 gene-related CAH arising from UPD of chromosome 1.
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Hiperplasia Suprarrenal Congénita/genética , Cromosomas Humanos Par 1/genética , Genes Recesivos , Progesterona Reductasa/genética , Disomía Uniparental , Hiperplasia Suprarrenal Congénita/enzimología , Análisis Mutacional de ADN , Homocigoto , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Masculino , Mutación Missense , Progesterona Reductasa/deficienciaRESUMEN
UNLABELLED: Patients and families living with metabolic disorders face challenging dietary and drug treatment regimens. On the hypothesis that poor palatability, volume and frequency of drug/formula administration contribute to treatment non-adherence and hyperammonemic episodes, a survey was conducted of patient, caregiver (CG) and physician perspectives on treatments used in urea cycle disorders (UCD). METHODS: A paper and online survey assessed experience with UCD medications, medical foods and dietary supplements. RESULTS: 25 physicians, 52 adult patients and 114 CG responded. In 2009, the most common UCD-specific intervention reported by patients included sodium phenylbutyrate (60%), followed by l-citrulline (46%), amino acid medical foods (15%), l-arginine preparations (18%), and sodium benzoate (8%). Only 36% of patients reported experiencing no hyperammonemic episodes in the last 2 years. The most commonly reported cause of hyperammonemic episodes was infection or other acute illnesses, followed by dietary indiscretion, side effects of medications, and drug non-adherence. Most patients, caregivers and physicians (> 75%) ranked nitrogen-scavenging medications, l-citrulline, l-arginine, and medical foods as "effective" or "very effective." Non-adherence was common (e.g. 18% of patients admitted to missing sodium phenylbutyrate "at least once a week" and "at least one a day"). Barriers to adherence included taste of medications, frequency of drug administration, number of pills, difficulty swallowing pills, side effects, forgetting to take medications, and high cost. Strategies to mitigate the gastrointestinal side effects of medications included the use of gastric tubes and acid reflux medications. Physicians indicated that 25% and 33% of pediatric and adult patients, respectively, were given less than the recommended dose of sodium phenylbutyrate due to concerns of tolerance, administration, and cost. CONCLUSIONS: Despite positive views of their effectiveness, respondents found medications, medical foods and dietary supplements difficult to take and viewed adherence as inadequate, thus contributing to hyperammonemic episodes.
RESUMEN
PURPOSE: Medical foods for methylmalonic acidemias (MMAs) and propionic acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. METHODS: Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). RESULTS: Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut(0): 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = -0.453; P = 0.014; R(2) = 0.209 and r = -0.341; P = 0.05; R(2) = 0.123, respectively). CONCLUSION: Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety.Genet Med 18 4, 386-395.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Dieta , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Aminoácidos de Cadena Ramificada , Composición Corporal , Pesos y Medidas Corporales , Niño , Preescolar , Estudios Transversales , Dieta/efectos adversos , Proteínas en la Dieta , Suplementos Dietéticos , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas. X-inactivation plays a major role in determining the range of phenotypic expression. Thus, patients can demonstrate a wide spectrum of disease severity, making accurate diagnosis more challenging. Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. We present a case of molecularly confirmed TODPD in a girl with the 47,XXX chromosomal complement and deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions. Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma, which contrasts with the dermal hypoplasia described in the only other such facial biopsy reported in the literature. The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology, which may explain the nature of many connective tissue pleotropic effects in FLNA-related disorders.
Asunto(s)
Anetodermia/genética , Fibroma Osificante/genética , Filaminas/genética , Dedos/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Deformidades Congénitas de las Extremidades/genética , Mutación , Osteocondrodisplasias/genética , Trastornos de la Pigmentación/genética , Dedos del Pie/anomalías , Anetodermia/complicaciones , Anetodermia/diagnóstico , Anetodermia/patología , Femenino , Fibroma Osificante/complicaciones , Fibroma Osificante/diagnóstico , Fibroma Osificante/patología , Dedos/patología , Expresión Génica , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Recién Nacido , Cariotipo , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/patología , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patología , Trastornos de la Pigmentación/complicaciones , Trastornos de la Pigmentación/diagnóstico , Trastornos de la Pigmentación/patología , Dedos del Pie/patología , Inactivación del Cromosoma XRESUMEN
OBJECTIVE: Hyperammonemic encephalopathy is an uncommon but severe complication of the Roux-en-Y gastric bypass surgery for obesity. Mechanisms underlying this complication are incompletely understood, resulting in delayed recognition and management. This study evaluated common laboratory findings and possible etiology of hyperammonemic encephalopathy after successful Roux-en-Y gastric bypass surgery. METHODS: A retrospective review of 20 patients identified through our own clinical practice was conducted, with the addition of similar cases from other institutions identified through the review of literature. RESULTS: Patients presenting with hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery presented with overlapping clinical and laboratory findings. Common features included: (1) weight loss following successful Roux-en-Y gastric bypass for obesity; (2) hyperammonemic encephalopathy accompanied by elevated plasma glutamine levels; (3) absence of cirrhosis; (4) hypoalbuminemia; and (5) low plasma zinc levels. The mortality rate was 50%. Ninety-five percent of patients were women. Three patients were diagnosed with proximal urea cycle disorders. One patient experienced improvement in the hyperammonemia after surgical correction of spontaneous splenorenal shunt. CONCLUSIONS: Hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery is a newly recognized, potentially fatal syndrome with diverse pathophysiologic mechanisms encompassing genetic and nongenetic causes.
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Anastomosis en-Y de Roux/efectos adversos , Derivación Gástrica/efectos adversos , Hiperamonemia/etiología , Obesidad Mórbida/cirugía , Adulto , Femenino , Humanos , Hiperamonemia/mortalidad , Masculino , Persona de Mediana Edad , Obesidad Mórbida/mortalidad , Estudios Retrospectivos , SíndromeRESUMEN
OBJECTIVE: Measurements of neonatal metabolites are commonly used in newborn screening (NBS) programs to detect inborn errors of metabolism. Variation in these metabolites, particularly in infants born preterm (<37 weeks gestation), can result from multiple etiologies. We sought to evaluate the impact of maternal complications of pregnancy and environmental stressors on NBS metabolites. METHODS: We examined 49 metabolic biomarkers obtained from routine NBS in 452 infants born preterm for association with maternal environmental stressors and complications of pregnancy. RESULTS: Neonatal free carnitine (C0, p = 1.4 × 10(-7)), acetylcarnitine (C2, p = 2.7 × 10(-7)), octenoylcarnitine (C8:1, p = 5.2 × 10(-11)) and linoleoylcarnitine (C18:2, p = 9.1 × 10(-7)) were elevated in infants born to preeclamptic mothers. Similar elevations were observed in small for gestational age infants and in infants where labor was not initiated prior to delivery. When accounting for all three factors, associations remained strongest between acylcarnitines and preeclampsia. CONCLUSION: We observed that maternal conditions, particularly preeclampsia, influence NBS biomarkers. This is important for identifying maternal conditions that influence metabolites measured during routine NBS that are also markers of fetal growth and overall health.
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Acetilcarnitina/sangre , Sangre Fetal/metabolismo , Tamizaje Neonatal , Preeclampsia/sangre , Alanina/sangre , Biomarcadores/sangre , Femenino , Humanos , Recién Nacido , Masculino , Análisis Multivariante , Embarazo , Estudios RetrospectivosRESUMEN
Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.
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Anomalías Múltiples/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Desarrollo Embrionario/genética , Proteínas del Tejido Nervioso/genética , Proteínas Represoras/genética , Alelos , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Enfermedades Cardiovasculares/genética , Cromosomas/efectos de los fármacos , Cromosomas/genética , Cromosomas Humanos Par 1/genética , Desarrollo Embrionario/efectos de los fármacos , Etilnitrosourea , Pérdida Auditiva/genética , Hipocampo/efectos de los fármacos , Hipocampo/embriología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , FenotipoRESUMEN
We report on a case of apparent germline mosaicism in a family of two sisters carrying a novel 19p13.13 deletion. The 11-year-old proposita was referred for evaluation of macrocephaly, moderate intellectual disability (ID), and episodic ataxia. Array comparative genomic hybridization (CGH) detected a 399 kb microdeletion with breakpoints within genes NFIX and CACNA1A. A similar deletion was also seen in the elder sibling who presented with macrocephaly, ID, and strabismus. The deletions were confirmed to be de novo after the parental aCGH analysis suggesting that this is an example of germinal mosaicism. This study contributes additional information for the newly identified 19p13 deletion syndrome and clarifies the clinical roles of genes in the involved region. This case of apparent germline mosaicism represents the only known family in the cohort of 1,800 patients analyzed by our group.
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Canales de Calcio/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 19/genética , Mutación de Línea Germinal , Discapacidad Intelectual/genética , Eliminación de Secuencia/genética , Adolescente , Hibridación Genómica Comparativa , Femenino , Humanos , Recién Nacido , Mosaicismo , SíndromeRESUMEN
BACKGROUND: Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity. METHODS: We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (<37 wk of gestational age) neonates. RESULTS: We observed higher levels of phenylalanine (PHE) in infants with respiratory distress syndrome (RDS; P = 1.7 × 10(-5)), the only association that was significant after correction for multiple testing. We found suggestive significance (P < 0.001) of higher essential amino acids in infants with patent ductus arteriosus (PDA). Functionality of these findings was explored in the ductus arteriosus (DA) isolated from term and preterm mouse pups. None of the amino acids had a direct vasodilatory effect on the isolated DA. CONCLUSION: We found that newborns with RDS had higher levels of PHE that may be a result of impaired PHE hydroxylase activity. We also detected marginally higher levels of all measured essential amino acids in infants with PDA. We did not find dilation of the mouse ductus for these metabolites, indicating that instead of potentially causing PDA, they are probably serving as markers of catabolism.
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Aminoácidos/metabolismo , Enfermedades del Recién Nacido/metabolismo , Recien Nacido Prematuro , Animales , Femenino , Humanos , Recién Nacido , Masculino , Ratones , Estudios Retrospectivos , Espectrometría de Masas en TándemRESUMEN
The FRAS1-related extracellular matrix 1 (FREM1) gene encodes an extracellular matrix protein that plays a critical role in the development of multiple organ systems. In humans, recessive mutations in FREM1 cause eye defects, congenital diaphragmatic hernia, renal anomalies and anorectal malformations including anteriorly placed anus. A similar constellation of findings-microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis and rectal prolapse-have been described in FREM1-deficient mice. In this paper, we identify a homozygous Frem1 missense mutation (c.1687A>T, p.Ile563Phe) in an N-ethyl-N-nitrosourea (ENU)-derived mouse strain, crf11, with microphthalmia, cryptophthalmos, renal agenesis and rectal prolapse. This mutation affects a highly conserved residue in FREM1's third CSPG domain. The p.Ile563Phe change is predicted to be deleterious and to cause decreased FREM1 protein stability. The crf11 allele also fails to complement the previously described eyes2 allele of Frem1 (p.Lys826*) providing further evidence that the crf11 phenotype is due to changes affecting Frem1 function. We then use mice bearing the crf11 and eyes2 alleles to identify lung lobulation defects and decreased anogenital distance in males as novel phenotypes associated with FREM1 deficiency in mice. Due to phenotypic overlaps between FREM1-deficient mice and mice that are deficient for the retinoic acid-responsive transcription factor GATA4 and the extracellular matrix protein SLIT3, we also perform experiments to look for in vivo genetic interactions between the genes that encode these proteins. These experiments reveal that Frem1 interacts genetically with Gata4 in the development of lung lobulation defects and with Slit3 in the development of renal agenesis. These results demonstrate that FREM1-deficient mice faithfully recapitulate many of the phenotypes seen in individuals with FREM1 deficiency and that variations in GATA4 and SLIT3 expression modulate some FREM1-related phenotypes in mice.
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Epistasis Genética , Proteínas de la Matriz Extracelular/genética , Factor de Transcripción GATA4/genética , Proteínas de la Membrana/genética , Fenotipo , Anomalías Múltiples/genética , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Anomalías Congénitas/genética , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/metabolismo , Factor de Transcripción GATA4/metabolismo , Regulación del Desarrollo de la Expresión Génica , Estudios de Asociación Genética , Haploinsuficiencia , Homocigoto , Riñón/anomalías , Enfermedades Renales/congénito , Enfermedades Renales/genética , Pulmón/embriología , Pulmón/metabolismo , Pulmón/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Mutación Missense , Alineación de SecuenciaRESUMEN
BACKGROUND: Elevations or deficits in thyroid hormone levels are responsible for a wide range of neonatal and adult phenotypes. Several genome-wide, candidate gene, and meta-analysis studies have examined thyroid hormones in adults; however, to our knowledge, no genetic association studies have been performed with neonatal thyroid levels. METHODS: A population of Iowa neonates, term (n = 827) and preterm (n = 815), were genotyped for 45 single-nucleotide polymorphisms (SNPs). Thyroid-stimulating hormone (TSH) values were obtained from the Iowa Neonatal Metabolic Screening Program. ANOVA was performed to identify genetic associations with TSH concentrations. RESULTS: The strongest association was rs4704397 in the PDE8B gene (P = 1.3 × 10(-4)), followed by rs965513 (P = 6.4 × 10(-4)) on chromosome 9 upstream of the FOXE1 gene. Both of these SNPs met statistical significance after correction for multiple testing. Six other SNPs were marginally significant (P < 0.05). CONCLUSION: We demonstrated for the first time two genetic associations with neonatal TSH levels that replicate findings with adult TSH levels. These SNPs should be considered early predictors of risk for adult diseases and conditions associated with thyroid hormone levels. Furthermore, this study provides a better understanding of the thyroid profile and potential risk for thyroid disorders in newborns.