RESUMO
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.
Assuntos
Transtorno do Espectro Autista , Biomarcadores , Deficiência Intelectual , Mitocôndrias , Acidemia Propiônica , Humanos , Acidemia Propiônica/genética , Biomarcadores/sangue , Masculino , Feminino , Criança , Deficiência Intelectual/genética , Mitocôndrias/metabolismo , Pré-Escolar , Adolescente , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/genética , Transtorno Autístico/metabolismo , Transtorno Autístico/genética , Adulto , Metilmalonil-CoA Descarboxilase/genética , Metilmalonil-CoA Descarboxilase/metabolismo , Adulto Jovem , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangue , CitratosRESUMO
The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 × 10-5 ). Using population data, we estimate that ~85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations.
Assuntos
Receptores de Superfície Celular , Transcobalaminas , Antígenos CD , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Receptores de Superfície Celular/genética , Transcobalaminas/genética , Transcobalaminas/metabolismo , Vitamina B 12/metabolismoRESUMO
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.
Assuntos
Argininossuccinato Liase/genética , Acidúria Argininossuccínica/genética , Células Endoteliais/patologia , Hipertensão/genética , Adolescente , Animais , Pressão Sanguínea/genética , Células Cultivadas , Criança , Modelos Animais de Doenças , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/genética , Óxido Nítrico/genética , Estresse Oxidativo/genética , Distúrbios Congênitos do Ciclo da Ureia/genéticaRESUMO
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.
Assuntos
Transplante de Fígado , Acidemia Propiônica , Biomarcadores , Humanos , Laboratórios , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/genéticaRESUMO
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.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Propionatos , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biomarcadores , Testes Respiratórios , Humanos , Fígado , Ácido MetilmalônicoRESUMO
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.
Assuntos
Acidemia Propiônica/complicações , Insuficiência Renal Crônica/epidemiologia , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Creatinina/sangue , Estudos Transversais , Cistatina C/análise , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Rim , Lipocalina-2/análise , Lipocalina-2/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Acidemia Propiônica/epidemiologia , Ácido Úrico/análise , Ácido Úrico/sangueRESUMO
BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Linfócitos B/citologia , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Hematológicas/imunologia , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Doenças Vestibulares/imunologia , Adolescente , Adulto , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Diferenciação Celular , Criança , Pré-Escolar , Humanos , Lactente , Mutação , Adulto JovemRESUMO
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.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Dieta , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Aminoácidos de Cadeia Ramificada , Composição Corporal , Pesos e Medidas Corporais , Criança , Pré-Escolar , Estudos Transversais , Dieta/efeitos adversos , Proteínas Alimentares , Suplementos Nutricionais , Gerenciamento Clínico , Feminino , Humanos , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ~86 kb FREM1 deletion that affects the expression of FREM1's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N-ethyl-N-nitrosourea -derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1(eyes2) mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1(eyes2) embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.
Assuntos
Diafragma/crescimento & desenvolvimento , Proteínas da Matriz Extracelular/genética , Hérnias Diafragmáticas Congênitas , Animais , Criança , Feminino , Genes Recessivos , Hérnia Diafragmática/genética , Hérnia Diafragmática/fisiopatologia , Homozigoto , Humanos , Camundongos , Nariz/anormalidades , Doenças Nasais/genética , Deleção de Sequência/genéticaRESUMO
Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.
Assuntos
Acidúria Argininossuccínica/tratamento farmacológico , Acidúria Argininossuccínica/fisiopatologia , Terapia Genética , Óxido Nítrico/deficiência , Óxido Nítrico/farmacologia , Adolescente , Animais , Arginina/sangue , Argininossuccinato Liase/genética , Acidúria Argininossuccínica/complicações , Acidúria Argininossuccínica/genética , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Fígado/enzimologia , Masculino , Camundongos , Óxido Nítrico/biossínteseAssuntos
Mielofibrose Primária/genética , Proteínas de Transporte Vesicular/deficiência , Anormalidades Múltiplas/genética , Transplante de Medula Óssea , Criança , Consanguinidade , Evolução Fatal , Feminino , Disgenesia Gonadal 46 XY/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo , Mielofibrose Primária/congênito , Mielofibrose Primária/terapia , Síndrome , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologiaRESUMO
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.
Assuntos
Anetodermia/genética , Fibroma Ossificante/genética , Filaminas/genética , Dedos/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deformidades Congênitas dos Membros/genética , Mutação , Osteocondrodisplasias/genética , Transtornos da Pigmentação/genética , Dedos do Pé/anormalidades , Anetodermia/complicações , Anetodermia/diagnóstico , Anetodermia/patologia , Feminino , Fibroma Ossificante/complicações , Fibroma Ossificante/diagnóstico , Fibroma Ossificante/patologia , Dedos/patologia , Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Recém-Nascido , Cariótipo , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/patologia , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Transtornos da Pigmentação/complicações , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/patologia , Dedos do Pé/patologia , Inativação do Cromossomo XRESUMO
Mutations in genes that play fundamental roles in metabolic pathways have been found to also play a role in tumor development and susceptibility to cancer. At the same time, significant progress has been made in the treatment of patients with inborn errors of metabolism (IEM),(1) resulting in increased longevity and the unmasking of cancer predisposition, frequently hepatocellular carcinoma, in these conditions. These patients offer a potential opportunity to deepen our understanding of how intermediary metabolism impacts tumorigenesis. We provide an overview from the perspective of cancers in patients affected with IEM and discuss how dysregulation of these specific metabolic pathways might contribute to the mechanisms of cancer development and treatment.
Assuntos
Erros Inatos do Metabolismo/complicações , Neoplasias/etiologia , Neoplasias/terapia , Carcinoma Hepatocelular/etiologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Redes e Vias Metabólicas/genética , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Modelos Biológicos , Mutação , Neoplasias/genética , Neoplasias/metabolismoRESUMO
Human skeletal dysplasias are disorders that result from errors in bone, cartilage, and joint development. A complex series of signaling pathways, including the FGF, TGFbeta, BMP, WNT, Notch, and Hedgehog pathways, are essential for proper skeletogenesis, and human skeletal dysplasias are often a consequence of primary or secondary dysregulation of these pathways. Although these pathways interact to regulate bone, cartilage, and joint formation, human genetic phenotypes point to the predominant action of specific components of these pathways. Mutations in the genes with a role in metabolic processing within the cell, the extracellular matrix, and transcriptional regulation can lead to dysregulation of cell-cell and cell-matrix signaling that alters tissue patterning, cell differentiation, proliferation, and apoptosis. We propose a morphogen rheostat model to conceptualize how mutations in different metabolic processes can lead to the integration of differential signaling inputs within a temporal and spatial context to generate apparently divergent skeletal phenotypes.
Assuntos
Doenças das Cartilagens/metabolismo , Artropatias/metabolismo , Doenças Musculoesqueléticas/metabolismo , Transdução de Sinais , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças das Cartilagens/embriologia , Doenças das Cartilagens/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Artropatias/embriologia , Artropatias/genética , Doenças Musculoesqueléticas/genéticaRESUMO
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.
Assuntos
Canais de Cálcio/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 19/genética , Mutação em Linhagem Germinativa , Deficiência Intelectual/genética , Deleção de Sequência/genética , Adolescente , Hibridização Genômica Comparativa , Feminino , Humanos , Recém-Nascido , Mosaicismo , SíndromeRESUMO
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.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/genética , Cromossomos Humanos Par 9 , Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/genética , Tireotropina/sangue , Análise de Variância , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Idade Gestacional , Haplótipos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Iowa , Masculino , Triagem Neonatal , Fenótipo , Fatores de RiscoRESUMO
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.
Assuntos
Aminoácidos/metabolismo , Doenças do Recém-Nascido/metabolismo , Recém-Nascido Prematuro , Animais , Feminino , Humanos , Recém-Nascido , Masculino , Camundongos , Estudos Retrospectivos , Espectrometria de Massas em TandemRESUMO
Orphan drug designation (ODD) is an important program intended to facilitate the development of orphan drugs in the United States. An orphan drug benefiting pediatric patients can qualify as a drug for a Rare Pediatric Disease Designation (RPDD) as well. The ODD and RPDD programs provide financial incentives for development of diagnostic drugs, preventive measures, and treatment of diseases affecting small patient populations (adult and pediatric) for which commercial development would otherwise be very challenging. In 2019, a multidisciplinary group of collaborators at National Institutes of Health (NIH) embarked upon a gene therapy platform program called Platform Vector Gene Therapy (PaVe-GT) intended to develop gene therapies for four such rare disorders. An important part of PaVe-GT is to publicly share scientific and regulatory experience gained at different stages during the implementation of the PaVe-GT platform utilizing illustrative examples. The PaVe-GT team recently obtained ODD and RPDD for an adeno-associated virus gene therapy to treat propionic acidemia. Given an increasing interest in obtaining ODD for gene therapy, especially by small companies, research investigators, and patient groups, we overview the submission process and subsequently provide examples of our ODD and RPDD applications. Our ODD and RPDD applications and templates can also be found on the PaVe-GT website. Shared reference documents will have great utility to assist parties who may have limited experience with the preparation of similar applications for their orphan product.