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1.
Cent Eur J Public Health ; 27(2): 153-159, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31241292

RESUMO

OBJECTIVES: Presymptomatic detection of patients with rare diseases (RD), defined by a population frequency less than 1 : 2,000, is the task of newborn screening (NBS). In the Czech Republic (CZ), currently eighteen RD are screened: phenylketonuria/hyperphenylalaninemia (PKU/HPA), congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), medium chain acyl-CoA dehydrogenase deficiency (MCADD), long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), very long chain acyl-CoA dehydrogenase deficiency (VLCADD), carnitine palmitoyl transferase I and II deficiency (CPTID, CPTIID), carnitine-acylcarnitine translocase deficiency (CACTD), maple syrup urine disease (MSUD), glutaric aciduria type I (GA I), isovaleryl-CoA dehydrogenase deficiency (IVA), argininemia (ARG), citrullinemia (CIT), biotinidase deficiency (BTD), cystathionine beta-synthase-deficient homocystinuria (CBSD HCU), and methylenetetrahydrofolate reductase deficiency homocystinuria (MTHFRD HCU). The aim was to analyze the prevalence of RD screened by NBS in CZ. METHODS: We examined the NBS programme in CZ from 1 January 2010 to 31 December 2017, which covered 888,891 neonates. Dried blood spots were primarily analyzed using fluorescence immuno-assay, tandem mass spectrometry and fluorimetry. RESULTS: The overall prevalence of RD among the neonate cohort was 1 : 1,043. Individually, 1 : 2,877 for CH, 1 : 5,521 for PKU/HPA, 1 : 6,536 for CF (1 : 5,887 including false negative patients), 1 : 12,520 for CAH, 1 : 22,222 for MCADD, 1 : 80,808 for LCHADD, 1 : 177,778 for GA I, 1 : 177,778 for IVA, 1 : 222,223 for VLCADD, 1 : 296,297 for MSUD, 1 : 8,638 for BTD, and 1 : 181,396 for CBSD HCU. CONCLUSIONS: The observed prevalence of RD, based on NBS, corresponds to that expected, more precisely it was higher for BTD and lower for MSUD, IVA, CBSD HCU, MCADD and VLCADD. Early detection of rare diseases by means of NBS is an effective secondary prevention tool.


Assuntos
Triagem Neonatal/métodos , Doenças Raras/epidemiologia , Biomarcadores/sangue , República Tcheca/epidemiologia , Fluorometria , Humanos , Recém-Nascido , Doenças Raras/sangue , Espectrometria de Massas em Tandem
2.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

3.
Eur J Pediatr ; 177(11): 1697-1704, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30136145

RESUMO

Neonates with low birthweight (LBW) represent a vulnerable population. This retrospective study analyzed the birth frequency of diseases detected by neonatal screening (NBS) in normal and LBW neonates in the Czech Republic. Between years 2002 and 2016, the number of screened disorders in the Czech Republic gradually increased from two to 13. Prevalence of screened diseases was calculated for cohorts ranging from 777,100 to 1,277,283 neonates stratified by birthweight. Odds ratio of the association of LBW with each disease was calculated and statistical significance was evaluated using the chi-square test or Fisher's exact test, as appropriate. Three diseases were associated with higher risk of prevalence in LBW neonates, namely congenital hypothyroidism (OR 2.50, CI 1.92; 3.25), cystic fibrosis (OR 2.44, CI 1.51; 3.94), and long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) (OR 7.74, CI 2.18; 27.42).Conclusion: Although the underlying mechanisms are not well understood, results can be hypothesized that LBW (respectively prematurity) may lead to the secondary and often transitory hypothyroidism while cystic fibrosis and LCHADD may manifest already prenatally and result into preterm birth and LBW. What is Known: • The percentage of low birthweight (LBW) neonates in the Czech Republic has been increasing. • Previously published studies reported positive association between LBW and congenital hypothyroidism and cystic fibrosis. What is New: • The association between LCHADD and LBW has not yet been described. • LBW can be the first manifestation of cystic fibrosis and LCHADD.


Assuntos
Doenças do Recém-Nascido/epidemiologia , Triagem Neonatal/normas , Peso ao Nascer , República Tcheca/epidemiologia , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Prevalência , Estudos Retrospectivos
4.
Appl Physiol Nutr Metab ; 40(3): 280-91, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25723909

RESUMO

The aim of this study was to estimate the effect of carnitine supplementation on lipid disorders and peripheral tissue insulin sensitivity in a non-obese animal model of insulin resistance, the hereditary hypertriglyceridemic (HHTg) rat. Male HHTg rats were fed a standard diet, and half of them received daily doses of carnitine (500 mg·kg(-1) body weight) for 8 weeks. Rats of the original Wistar strain were used for comparison. HHTg rats exhibited increased urinary excretion of free carnitine and reduced carnitine content in the liver and blood. Carnitine supplementation compensated for this shortage and promoted urinary excretion of acetylcarnitine without any signs of (acyl)carnitine accumulation in skeletal muscle. Compared with their untreated littermates, carnitine-treated HHTg rats exhibited lower weight gain, reduced liver steatosis, lower fasting triglyceridemia, and greater reduction of serum free fatty acid content after glucose load. Carnitine treatment was associated with increased mitochondrial biogenesis and oxidative capacity for fatty acids, amelioration of oxidative stress, and restored substrate switching in the liver. In skeletal muscle (diaphragm), carnitine supplementation was associated with significantly higher palmitate oxidation and a more favorable complete to incomplete oxidation products ratio. Carnitine supplementation further enhanced insulin sensitivity ex vivo. No effects on whole-body glucose tolerance were observed. Our data suggest that some metabolic syndrome-related disorders, particularly fatty acid oxidation, steatosis, and oxidative stress in the liver, could be attenuated by carnitine supplementation. The effect of carnitine could be explained, at least partly, by enhanced substrate oxidation and increased fatty acid transport from tissues in the form of short-chain acylcarnitines.


Assuntos
Carnitina/farmacologia , Hipertrigliceridemia/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Carnitina/administração & dosagem , Carnitina/análogos & derivados , Carnitina/sangue , Carnitina/metabolismo , Carnitina/urina , DNA Mitocondrial/genética , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Predisposição Genética para Doença , Homeostase , Hipertrigliceridemia/metabolismo , Resistência à Insulina , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Ratos
5.
Clin Chim Acta ; 437: 211-7, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25086281

RESUMO

BACKGROUND: Disorders of homocysteine and B-vitamin metabolism represent a significant problem in clinical practice. Establishing the diagnosis requires specialized tests with demanding preanalytical requirements. To advance the detection of patients with these disorders, we developed a method for the simultaneous determination of cystathionine (Cysta), methionine (Met) and total homocysteine (tHcy) in dried blood spots (DBSs). METHODS: A punch from a DBS sample was mixed with a solution of isotopically labeled internal standards, and analytes were extracted using methanol/0.1% formic acid/0.5mol/L dithiothreitol. The extract was injected into an LC-MS/MS system operating in MRM mode. RESULTS: The analytical performance of the method employing DBS is adequate for its purpose and the type of sample. Compared with Cysta, tHcy and Met plasma levels, our method exhibited a negative bias between -3.8% and -42.2% due to the lower concentrations of these analytes in erythrocytes. The tHcy level and the Met/Cysta ratio in DBS enabled the clear detection of 12 patients with disorders of transsulfuration and with genetic and nutritional remethylation defects. CONCLUSIONS: The ease of collecting and transporting DBS samples may advance diagnostic procedures in patients with neuropsychiatric disorders and thromboembolism. Consequently, this approach may facilitate detection and simplify the monitoring of patients with homocystinuria.


Assuntos
Cistationina/sangue , Teste em Amostras de Sangue Seco/métodos , Homocisteína/sangue , Homocistinúria/sangue , Metionina/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Cromatografia Líquida/estatística & dados numéricos , Gerenciamento Clínico , Teste em Amostras de Sangue Seco/estatística & dados numéricos , Feminino , Homocistinúria/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Espectrometria de Massas em Tandem/estatística & dados numéricos
6.
Genet Med ; 14(7): 648-55, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22766634

RESUMO

PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.


Assuntos
Triagem Neonatal/métodos , Software , Espectrometria de Massas em Tandem/métodos , Biologia Computacional , Interpretação Estatística de Dados , Bases de Dados Factuais , Diagnóstico Diferencial , Reações Falso-Positivas , Humanos , Recém-Nascido , Cooperação Internacional , Metaboloma , Minnesota , Análise Multivariada , Reconhecimento Automatizado de Padrão , Valor Preditivo dos Testes , Estudos Retrospectivos
7.
Genet Med ; 13(3): 230-54, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21325949

RESUMO

PURPOSE: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25­30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.


Assuntos
Doenças Metabólicas/diagnóstico , Triagem Neonatal , Espectrometria de Massas em Tandem , Aminoácidos/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Humanos , Recém-Nascido , Cooperação Internacional , Valores de Referência , Sensibilidade e Especificidade , Software
8.
Cas Lek Cesk ; 149(9): 411-6, 2010.
Artigo em Tcheco | MEDLINE | ID: mdl-21117323

RESUMO

BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive inborn error of metabolism caused by deficiency of fumarylacetoacetate hydrolase. HT1 manifests with severe liver and kidney impairment and associates with an increased risk of liver cancer development. The aim of our study is to present a detailed clinical picture and results of biochemical and molecular genetic analyses in 11 Czech patients with HT1 diagnosed in our clinic within 1982-2006. METHODS AND RESULTS: In 9 patients the disease manifested between 1.5-7 months of age with refusal to eat, failure to thrive and vomiting. In 4 children HT1 progressed to acute liver failure. One clinically healthy boy was diagnosed because of affected sister. In one boy with liver cirrhosis the diagnosis was delayed until the age of 5.5 years. In all children the biochemical investigation showed elevated liver enzymes, alpha1-fetoprotein and hypophosphatemic rickets. Metabolic investigation revealed increased plasma tyrosine level, urinary excretion of succinylacetone and in 8 measured patients also increased urinary delta-aminolevulinic acid concentration. Three patients born before 1988 died due to liver cancer development (two of them) or liver failure. The average age of our 8 living patients is 10.7 +/- 8.3 years. Mutation analysis of FAH gene confirmed the HT1 in these patients and three novel mutations were found in FAH gene: c.579C>A, c.680G>T and c.1210G>A. Clinical status in six patients is favourable on strict low protein diet combined with Orfadin therapy. However, in two children despite of the maximal available therapy lasting 2 and 10 years resp., the disease progressed towards liver cancer development and necessity of liver transplantation. CONCLUSIONS: Early diagnostics of HT1 as a part of extended newborn screening is the only possibility to further improve the prognosis of the patients. Moreover, available molecular-genetic analysis of the FAH gene enables prenatal diagnostics in affected families.


Assuntos
Tirosinemias/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Hidrolases/genética , Lactente , Masculino , Mutação , Tirosinemias/genética , Tirosinemias/metabolismo , Tirosinemias/terapia
9.
Am J Med Genet A ; 149A(4): 613-21, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19267410

RESUMO

Prosaposin deficiency (pSap-d) and saposin B deficiency (SapB-d) are both lipid storage disorders caused by mutations in the PSAP gene that codes for the 65-70 kDa prosaposin protein, which is the precursor for four sphingolipid activator proteins, saposins A-D. We report on two new patients with PSAP gene defects; one, with pSap-d, who had a severe neurovisceral dystrophy and died as a neonate, and the other with SapB-d, who presented with a metachromatic leukodystrophy-like disorder but had normal arylsulfatase activity. Screening for urinary sphingolipids was crucial to the diagnosis of both patients, with electrospray ionization tandem mass spectrometry also providing quantification. The pSap-d patient is the first case with this condition where urinary sphingolipids have been investigated. Multiple sphingolipids were elevated, with globotriaosylceramide showing the greatest increase. Both patients had novel mutations in the PSAP gene. The pSap-d patient was homozygous for a splice-acceptor site mutation two bases upstream of exon 10. This mutation led to a premature stop codon and yielded low levels of transcript. The SapB-d patient was a compound heterozygote with a splice-acceptor site variant exclusively affecting the SapB domain on one allele, and a 2 bp deletion leading to a null, that is, pSap-d mutation, on the other allele. Phenotypically, pSap-d is a relatively uniform disease of the neonate, whereas SapB-d is heterogeneous with a spectrum similar to that in metachromatic leukodystrophy. The possible existence of genotypes and phenotypes intermediate between those of pSap-d and the single saposin deficiencies is speculated.


Assuntos
Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/metabolismo , Mutação , Saposinas/deficiência , Saposinas/genética , Esfingolipídeos/urina , Encéfalo/anormalidades , Encéfalo/patologia , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Leucodistrofia Metacromática/patologia , Imagem por Ressonância Magnética , Masculino , Sítios de Splice de RNA/genética , Deleção de Sequência , Pele/patologia
10.
Clin Chim Acta ; 350(1-2): 99-106, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15530465

RESUMO

BACKGROUND: Electrospray tandem mass spectrometry (TMS) is a very powerful tool that enables one to perform high sample throughput analysis. This paper describes a method to determine creatinine in urine by tandem mass spectrometry with direct sample infusion into an ion source. METHODS: Samples (50 microl) were diluted with internal standard (IS) (450 microl of 0.667 mmol/l deuterated creatinine). Diluted samples were introduced into mass spectrometer with no prior pretreatment and after purification on ion-exchange 96-column cartridge. Tandem mass spectrometry analyses were performed in selected reaction monitoring mode. Creatinine and creatinine-d(3) were monitored using precursor and product ion settings (m/z 114 to 86 and m/z 117 to 89, respectively). The time of an analysis was 3.015 min. Both TMS methods were compared mutually and with the results obtained by enzymatic and Jaffe method. RESULTS: Linearity was obtained in the range 0.06-60 mmol/l. Detection limit was 0.2 mumol/l and recoveries were in the range 95.1-98.3% for both the assays with and without ion-exchange column. Results of both assays are in good agreement with those obtained by enzymatic and Jaffe method based on log-transformed Bland-Altman plots. Electrospray tandem mass spectrometry method utilizing both approaches with and without ion-exchange column is acceptable according to CLIA criteria. CONCLUSION: Tandem mass spectrometry allows rapid, sensitive and selective determination of creatinine in untreated urine.


Assuntos
Creatinina/urina , Espectrometria de Massas por Ionização por Electrospray/métodos , Cromatografia por Troca Iônica , Creatinina/normas , Técnica de Imunoensaio Enzimático de Multiplicação , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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