RESUMO
Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.
Assuntos
Erros Inatos do Metabolismo , Acidemia Propiônica , Humanos , Recém-Nascido , Triagem Neonatal/métodos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Espectrometria de Massas em Tandem/métodos , Carnitina/metabolismoRESUMO
We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.
Assuntos
Carboxiliases/genética , Peptídeo Sintases/genética , Purinas/metabolismo , Anormalidades Múltiplas/genética , Adenilossuccinato Liase/deficiência , Transtorno Autístico , Carboxiliases/metabolismo , Dinamarca , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Mutação , Peptídeo Sintases/metabolismo , Morte Perinatal , Fenótipo , Erros Inatos do Metabolismo da Purina-Pirimidina , Purinas/biossínteseRESUMO
Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31 P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak ßHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31 P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03011203.
Assuntos
Bebidas , Exercício Físico , Doença de Depósito de Glicogênio Tipo III/dietoterapia , Cetose/induzido quimicamente , Doenças Musculares/dietoterapia , Adulto , Glicemia/análise , Metabolismo dos Carboidratos , Estudos Cross-Over , Dieta Cetogênica , Carboidratos da Dieta , Ésteres/administração & dosagem , Feminino , Doença de Depósito de Glicogênio Tipo III/metabolismo , Humanos , Cetonas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Países Baixos , FenótipoRESUMO
Primary carnitine deficiency (PCD) affects fatty acid oxidation and is associated with cardiomyopathy and cardiac arrhythmia, but the risk of sudden death in PCD is unknown. The Faroe Islands have a high prevalence of PCD, 1:300. This study systematically investigated a possible association between untreated PCD and sudden death in young Faroese subjects. We investigated all medico-legal cases of sudden death between 1979 and 2012 among subjects below the age of 45. Stored biomaterial was examined with molecular genetic analysis to reveal PCD. We compared the prevalence of PCD among sudden death cases with that of the background population (0.23%) to calculate the odds ratio (OR) for sudden death with PCD. Biomaterial was available and genetically analyzed from 53 of 65 sudden death cases (82%) in the Faroe Islands. Six (one male and five females) of the 53 cases were homozygous for the PCD related c.95A>G mutation-a prevalence of 11.3% (95% CI 5%-23%) and an OR of 54.3 (95% CI 21-138, P < .0001) for the association between sudden death and untreated PCD. Only 11 of the 53 sudden death cases were women-of whom five were homozygous for the c.95A>G mutation (45.5%) yielding an OR of 348.8 (95% CI 94-1287, P < .0001) for the association between sudden death and untreated PCD in females. This study showed a strong association between sudden death and untreated PCD, especially in females.
Assuntos
Arritmias Cardíacas/etiologia , Cardiomiopatias/complicações , Carnitina/deficiência , Morte Súbita Cardíaca/etiologia , Hiperamonemia/complicações , Doenças Musculares/complicações , Adolescente , Adulto , Cardiomiopatias/genética , Carnitina/genética , Criança , Pré-Escolar , Dinamarca , Feminino , Homozigoto , Humanos , Hiperamonemia/genética , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doenças Musculares/genética , Mutação , Fatores Sexuais , Adulto JovemRESUMO
Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.
Assuntos
Doença de Depósito de Glicogênio Tipo III/diagnóstico , Doença de Depósito de Glicogênio Tipo III/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Genótipo , Sistema da Enzima Desramificadora do Glicogênio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Insufficient supply of vitamin D during early development may negatively affect offspring growth. METHODS: We examined the association between umbilical cord (UC) serum 25-hydroxyvitamin D (25(OH)D) concentrations and infant size in a study of two Faroese birth cohorts of 1038 singleton infants. In the third trimester, the pregnant women completed questionnaires, and clinical examination included birthweight, head circumference, and infant length at age 14 days. RESULTS: Fifty-three percent of the newborn population had UC 25(OH)D < 25 nmol/L as determined by LC-MS/MS. Using multiple linear regression models with adjustment for pre-pregnancy BMI, sex, parity, gestational age, or infant age at examination, season of birth, smoking, gestational diabetes, examiner, and cohort identity, we found no relationship between birthweight or head circumference and UC 25(OH)D. However, infants with vitamin D status <12 nmol/L had a 0.49 (95% confidence interval 0.05, 0.93) cm lower length than infants with vitamin D status >50 nmol/L in models further adjusted for birthweight. CONCLUSION: Our data suggest that umbilical cord serum 25(OH)D concentrations are positively associated with infant length but not with birthweight and head circumference. Although the paediatric relevance of the observed association is unclear, the possible long-term consequences of late-pregnancy hypovitaminosis D deserve attention.
Assuntos
Sangue Fetal/química , Retardo do Crescimento Fetal/etiologia , Complicações na Gravidez/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adulto , Peso ao Nascer , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/epidemiologia , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/epidemiologia , Inquéritos e Questionários , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologiaRESUMO
BACKGROUND: The existing literature on the association between measles vaccination and subsequent risk of allergic disease is inconclusive. The aim of this study was, therefore, to determine whether measles, mumps, and rubella (MMR) vaccination administered in early childhood was associated with asthma and allergic diseases at ages 5, 7 and 13 yrs in a birth cohort. METHODS: In the Faroe Islands, 640 children were followed from birth. Follow-up examinations at ages 5, 7 and 13 yrs included a physical examination and a maternal questionnaire about the child's health. At age 7, total and grass-specific IgE was quantified in the child's serum, and at age 13, the children underwent skin prick tests (SPT). The child's vaccination card was reviewed at examinations. RESULTS: At age 5, 533 of 555 children had been vaccinated for MMR. After confounder adjustment, we found early life MMR vaccination to be associated with a two-third reduction in the odds of asthma (OR: 0.33, 95% CI: 0.12; 0.90) and hypersensitivity/allergy (OR: 0.32, 95% CI: 0.11; 0.88) at age 5, and the substantially decreased odds of asthma were replicated at age 13 (OR: 0.22, 95% CI: 0.08; 0.56). At age 7, serum total IgE was reduced by 62.8% (CI 95%: -84.3%; -11.9%) in the vaccinated children. MMR vaccination was not significantly associated with allergic rhinoconjuctivitis symptoms, eczema, or SPT reactions at age 13. CONCLUSIONS: MMR vaccination early in life may have a protective effect against allergy at least up to age 7 and against asthma through age 13 yrs.
Assuntos
Asma/epidemiologia , Hipersensibilidade/epidemiologia , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Adolescente , Asma/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca , Feminino , Seguimentos , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Incidência , Masculino , Vacinação/estatística & dados numéricosRESUMO
BACKGROUND: Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal POP exposures and increased BMI, waist circumference and change in BMI from 5 to 7 years of age, though only among girls with overweight mothers. OBJECTIVES: In the same birth cohort, we investigated whether prenatal POP exposure was associated with serum concentrations of insulin and leptin among 5-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. METHODS: The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB), were measured in maternal pregnancy serum and breast milk. Children were followed-up at the age of 5 years where a non-fasting blood sample was drawn; 520 children (273 boys and 247 girls) had adequate serum amounts available for biomarker analyses by Luminex® technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age 5 while taking into account confounders. RESULTS: Girls with highest prenatal POP exposure were more likely to have high non-fasting insulin levels (PCBs 4th quartile: OR=3.71; 95% CI: 1.36, 10.01. DDE 4th quartile: OR=2.75; 95% CI: 1.09, 6.90. HCB 4th quartile: OR=1.98; 95% CI: 1.06, 3.69) compared to girls in the lowest quartile. No significant associations were observed with leptin, or among boys. A mediating effect of insulin or leptin on later obesity was not observed. CONCLUSION: These findings suggest, that for girls, prenatal exposure to POPs may play a role for later development of metabolic diseases by affecting the level of insulin.
Assuntos
Disruptores Endócrinos/análise , Exposição Ambiental/análise , Hidrocarbonetos Clorados/análise , Insulina/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Criança , Pré-Escolar , Estudos de Coortes , Disruptores Endócrinos/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Hidrocarbonetos Clorados/efeitos adversos , Leptina/sangue , Modelos Logísticos , Masculino , Obesidade/sangue , Obesidade/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Estudos Prospectivos , Fatores SexuaisRESUMO
BACKGROUND: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation and has been associated to episodes of sudden death in the Faroe Islands. Data are presented from the nationwide population based Faroese screening program to find people with low carnitine levels indicating PCD. METHODS: Whole blood samples from dried blood spots were analysed by tandem mass spectrometry with and without butylation. Genetic analyses were performed in all people with non-butylated free carnitine (fC0) below 7 µmol/L. RESULTS: 55 % (n = 26,462) of the entire population was screened and 89 PCD patients were identified, yielding an overall prevalence of 1:297 of PCD in the Faroe Islands. Carnitine levels were positively correlated to age in both males and females (p < 0.003) although levels decreased in females when reaching fertile age. The gender difference in mean carnitine levels was significant during female fertile age (4.71 µmol/L fC0 in the age group 25-30 years, p < 0.01). A lower cut-off of 5 µmol/L in fC0 identified all homozygous for the severe genotype c.95A > G (p.N32S) (n = 20). CONCLUSION: Carnitine levels differ by gender and age. A lower cut-off of 5 µmol/L in fC0 was appropriate to identify c.95A > G homozygotes. The prevalence of PCD in the Faroe Islands is the highest reported in the world (1:297).
Assuntos
Cardiomiopatias/sangue , Carnitina/sangue , Carnitina/deficiência , Hiperamonemia/sangue , Doenças Musculares/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Carnitina/genética , Criança , Pré-Escolar , Dinamarca , Teste em Amostras de Sangue Seco/métodos , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/genética , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Adulto JovemRESUMO
Inherited neuromuscular disorders affect approximately one in 3,500 children. Structural muscular defects are most common; however functional impairment of skeletal and cardiac muscle in both children and adults may be caused by inborn errors of energy metabolism as well. Patients suffering from metabolic myopathies due to compromised energy metabolism may present with exercise intolerance, muscle pain, reversible or progressive muscle weakness, and myoglobinuria. In this review, the physiology of energy metabolism in muscle is described, followed by the presentation of distinct disorders affecting skeletal and cardiac muscle: glycogen storage diseases types III, V, VII, fatty acid oxidation defects, and respiratory chain defects (i.e., mitochondriopathies). The diagnostic work-up and therapeutic options in these disorders are discussed.
Assuntos
Metabolismo Energético , Erros Inatos do Metabolismo , Músculos , Miopatias Congênitas Estruturais , Humanos , Músculos/metabolismo , Músculos/fisiologia , Músculos/fisiopatologiaRESUMO
We report a Caucasian neonate with chronic non-spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work-up failed to reveal other specific factors contributing to cholestasis. Severe hemolytic disease of the newborn may cause cholestasis even in the absence of associated primary hepato-biliary disease.
Assuntos
Anemia Hemolítica Congênita não Esferocítica/complicações , Colestase/etiologia , Deficiência de Glucosefosfato Desidrogenase/complicações , Recém-Nascido Prematuro , Icterícia Neonatal/etiologia , Kernicterus/complicações , Mutação de Sentido Incorreto , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Hemolítica Congênita não Esferocítica/patologia , Colestase/patologia , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/patologia , Humanos , Recém-Nascido , Icterícia Neonatal/patologia , Kernicterus/genética , Kernicterus/patologia , MasculinoRESUMO
Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-B and lymphocyte mAChRs as potential markers of exposure to these neurotoxicants. The blood neurotoxicity biomarkers were compared with prenatal and current exposures and with neuropsychological test results. Both biomarkers showed homogeneous distributions within this cohort (mAChR, range 0.04-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol mg(-1) protein h(-1)). No correlation was found between the two biomarkers and either blood neurotoxicant concentrations or clinical findings. MAO-B and mAChR sensitivity may not be sufficiently high to assess early, subclinical responses to low/moderate methylmercury and/or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents.
Assuntos
Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Linfócitos/metabolismo , Compostos de Metilmercúrio/toxicidade , Monoaminoxidase/metabolismo , Bifenilos Policlorados/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Plaquetas/enzimologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Testes Neuropsicológicos , GravidezRESUMO
One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G --> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
Assuntos
Surdez/genética , Doença de Leigh/genética , Ácido Metilmalônico/urina , Encefalomiopatias Mitocondriais/genética , Hipotonia Muscular/genética , Succinato-CoA Ligases/genética , Ilhas Atlânticas/epidemiologia , Encéfalo/patologia , Carnitina/sangue , Carnitina/urina , Análise Mutacional de DNA/métodos , DNA Mitocondrial/genética , Surdez/epidemiologia , Surdez/metabolismo , Saúde da Família , Feminino , Frequência do Gene/genética , Humanos , Lactente , Doença de Leigh/epidemiologia , Doença de Leigh/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Ácido Metilmalônico/sangue , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/metabolismo , Hipotonia Muscular/epidemiologia , Hipotonia Muscular/metabolismo , Músculo Esquelético/enzimologia , Mutação/genética , LinhagemRESUMO
Although hyperinsulinism is the predominant inherited cause of hypoglycemia in the newborn period, inborn errors of metabolism are the primary etiologies after 1 month of age. Disorders of carbohydrate metabolism often present with hypoglycemia when fasting occurs. The presentation, diagnosis, and management of the hepatic glycogen storage diseases and disorders of gluconeogenesis are reviewed.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Gluconeogênese/fisiologia , Hipoglicemia/etiologia , Glicemia/fisiologia , Erros Inatos do Metabolismo dos Carboidratos/complicações , Erros Inatos do Metabolismo dos Carboidratos/terapia , Humanos , Hipoglicemia/terapia , Lactente , Recém-NascidoRESUMO
Current knowledge on obesogenic effects of persistent organic pollutants (POPs) is equivocal. We therefore evaluated the associations between early-life POP exposures and body mass index (BMI) in 444 Faroese children born in 2007-2009. POPs were measured in maternal 2-week postpartum serum and child age-5 serum. Linear regression and generalised linear models assessed the associations with continuous and dichotomous BMI z-scores, respectively, at ages 18 months and/or 5 years. Maternal serum concentrations of HCB, PFOS and PFOA were associated with increased BMI z-scores and/or overweight risk (i.e. BMI z-score≥85th WHO percentile). No clear association was found for maternal serum-PCBs, p,p'-DDE, PFHxS, PFNA and PFDA. In cross-sectional analyses, we observed a pattern of inverse associations between child serum-POPs and BMI z-scores at age 5, perhaps due to reverse causation that requires attention in future prospective analyses. Findings in this recent cohort support a role of maternal exposure to endocrine disruptors in the childhood obesity epidemic.
Assuntos
Disruptores Endócrinos/toxicidade , Exposição Ambiental/efeitos adversos , Fluorocarbonos/toxicidade , Sobrepeso/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Antropometria , Pré-Escolar , Dinamarca/epidemiologia , Disruptores Endócrinos/sangue , Exposição Ambiental/análise , Feminino , Fluorocarbonos/sangue , Humanos , Lactente , Sobrepeso/sangue , Sobrepeso/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , PrevalênciaRESUMO
BACKGROUND: Gestational diabetes mellitus (GDM) is associated with increased availability of glucose and macronutrients in fetal circulation and macrosomia. Therefore, the role of GDM in the association between metabolism-disrupting chemicals and birth size deserves attention. OBJECTIVE: We examined whether GDM may mediate or modify the associations between maternal environmental pollutant exposures and offspring birth size measures. METHODS: We analyzed 604 Faroese pregnant women and their offsprings born in 1997-2000. Maternal pregnancy serum concentrations of organochlorine compounds (OCs: polychlorinated biphenyl (PCB) congeners and dichlorodiphenyldichloroethylene (DDE)), and five perfluoroalkyl substances (PFASs), and hair and cord blood mercury concentrations were measured. We used regression (single-pollutants) and structural equation models (SEMs) (multiple-pollutant analyses using latent constructs of OCs, PFASs and mercury) to estimate the associations with GDM and birth size measures, accounting for mediation and/or effect modification by GDM. RESULTS: Serum-DDE and hair-mercury concentrations were associated with GDM (adjusted OR per concentration doubling: 1.29; 95% CI: 0.94, 1.77 for DDE, and 0.79; 95% CI: 0.62, 0.99 for mercury), but in multiple pollutant-adjusted SEMs only a positive association between OC exposure and GDM remained significant (change in GDM odds per OC doubling: 0.45; 95% CI: 0.05, 0.86). PCB and overall OC exposure were positively associated with head circumference (SEM; mean change per OC doubling: 0.13cm; 95% CI, 0.01. 0.25). Overall PFAS exposure was inversely associated with birth weight (SEM; mean change per PFAS doubling: -169g; 95% CI: -359, 21), and for many single-PFASs we found a pattern of inverse associations with birth weight and head circumference in boys, and positive or null associations in girls. None of the environmental pollutants was associated with offspring length. GDM neither modified nor mediated the associations with birth size measures. CONCLUSIONS: We found associations with GDM and offspring birth size to be specific to the environmental pollutant or pollutant group. Associations with birth size measures appear to be independent of GDM occurrence.
Assuntos
Peso ao Nascer , Diabetes Gestacional/epidemiologia , Poluentes Ambientais/sangue , Exposição Materna , Adulto , Diabetes Gestacional/sangue , Poluentes Ambientais/análise , Feminino , Sangue Fetal/química , Macrossomia Fetal/sangue , Fluorocarbonos/sangue , Humanos , Hidrocarbonetos Clorados/sangue , Recém-Nascido , Masculino , Mercúrio/análise , Mercúrio/sangue , Gravidez/sangue , Adulto JovemRESUMO
Primary carnitine deficiency (PCD) causes low levels of carnitine in patients potentially leading to metabolic and cardiac symptoms. Newborn screening for PCD is now routine in many countries by measuring carnitine levels in infants. In this study we report Apgar scores, length and weight in newborns with PCD and newborns born to mothers with PCD compared to controls. Furthermore we report how effective different screening algorithms have been to detect newborns with PCD in the Faroe Islands. RESULTS: Newborns with PCD and newborns born to mothers with PCD did not differ with regard to Apgar scores, length and weight compared to controls. Newborns with PCD and newborns born to mothers with PCD had significantly lower levels of free carnitine (fC0) than controls. Screening algorithms focusing only on fC0 had a high rate of detection of newborns with PCD. Sample collection 4-9 days after birth seems to result in a higher detection rate than the current 2-3 days. CONCLUSION: The clinical status at birth in infants with PCD and infants born to mothers with PCD does not differ compared to control infants. Screening algorithms for PCD should focus on fC0, and blood samples should be taken when the maternal influence on fC0 has diminished.
RESUMO
The aim of this study was to determine whether maternal exposure to persistent perfluoroalkyl substances (PFASs) affect the capability to breastfeed. In two Faroese birth cohorts (N=1130), concentrations of five PFASs were measured in maternal serum during pregnancy or two weeks after term. Duration of breastfeeding was assessed by questionnaire and clinical interview. In adjusted linear regression models, a doubling of maternal serum PFASs was associated with a reduction in duration of both total and exclusive breastfeeding, most pronounced for perfluorooctane sulfonic acid (PFOS) where a doubling was associated with a reduction in total breastfeeding of 1.4 (95% CI: 0.6; 2.1) months and perfluorooctanoic acid (PFOA) where a doubling was associated with a reduction in exclusive breastfeeding of 0.5 (0.3; 0.7) months. The associations were evident among both primiparous and multiparous women, and thus cannot be explained by confounding from previous breastfeeding.
Assuntos
Ácidos Alcanossulfônicos/efeitos adversos , Ácidos Alcanossulfônicos/sangue , Aleitamento Materno/tendências , Poluentes Ambientais/efeitos adversos , Poluentes Ambientais/sangue , Fluorocarbonos/efeitos adversos , Fluorocarbonos/sangue , Exposição Materna/efeitos adversos , Estudos de Coortes , Dinamarca , Feminino , Humanos , Recém-Nascido , Fatores de TempoRESUMO
Perfluoroalkyl substances (PFASs) are highly persistent chemicals that might be associated with asthma and allergy, but the associations remain unclear. Therefore, this study examined whether pre- and postnatal PFAS exposure was associated with childhood asthma and allergy. Measles, mumps, and rubella (MMR) vaccination in early life may have a protective effect against asthma and allergy, and MMR vaccination is therefore taken into account when evaluating these associations. In a cohort of Faroese children whose mothers were recruited during pregnancy, serum concentrations of five PFASs - Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) - were measured at three timepoints (maternal serum in pregnancy week 34-36 and child serum at ages 5 and 13 years) and their association with immunoglobulin E (IgE) (cord blood and at age 7 years) and asthma/allergic diseases (questionnaires at ages 5 and 13 years and skin prick test at age 13 years) was determined. A total of 559 children were included in the analyses. Interactions with MMR vaccination were evaluated. Among 22 MMR-unvaccinated children, higher levels of the five PFASs at age 5 years were associated with increased odds of asthma at ages 5 and 13. The associations were reversed among MMR-vaccinated children. Prenatal PFAS exposure was not associated with childhood asthma or allergic diseases regardless of MMR vaccination status. In conclusion, PFAS exposure at age 5 was associated with increased risk of asthma among a small subgroup of MMR-unvaccinated children but not among MMR-vaccinated children. While PFAS exposure may impact immune system functions, this study suggests that MMR vaccination might be a potential effect-modifier.
Assuntos
Asma/imunologia , Fluorocarbonos/efeitos adversos , Hipersensibilidade/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca , Exposição Ambiental/efeitos adversos , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Lactente , Masculino , Gravidez , Testes Cutâneos , VacinaçãoRESUMO
BACKGROUND: Perfluorinated alkyl substances (PFAS) are suspected endocrine disruptors that are highly persistent and neurotoxic in animals. Human epidemiological studies of exposure-related deviations of children's behaviors are sparse. We assessed the associations between prenatal, 5- and 7-year PFAS exposures and behavioral problem scores in 7-year Faroese children. METHODS: Concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonic acid (PFHxS) were measured in maternal serum and in serum from children at ages 5 and 7years (n=539, 508, and 491, respectively). We used multivariable regressions and structural equations models to estimate the covariate-adjusted associations between serum-PFAS concentrations and behavioral difficulties, as assessed by the strengths and difficulties questionnaire (SDQ) at age 7. RESULTS: Serum-PFOS and PFHxS concentrations declined over time, whereas PFOA, PFNA, and PFDA tended to increase. No associations were observed between prenatal PFAS concentrations and SDQ scores. However, a two-fold increase in 5-year serum-PFOA, PFNA, and PFDA concentrations was associated with increases in total SDQ scores by 1.03 (95% CI: 0.11, 1.95), 0.72 (95% CI: 0.07, 1.38) and 0.78 points (95% CI: 0.01, 1.55), respectively. For SDQ subscales, significant associations were found in regard to hyperactivity, peer relationship, and conduct problems, as well as internalizing and externalizing problems and autism screening composite scores. Cross-sectional analyses at age 7years showed possible sex-dimorphic associations between PFAS concentrations and SDQ scores, where girls had consistently positive associations with SDQ scores whereas boys exhibited a pattern of negative or null associations. CONCLUSIONS: Higher serum PFAS concentrations at ages 5- and 7-years, but not prenatally, were associated with parent-reported behavioral problems at age 7.