RESUMO
The carnitine transporter defect is a potentially fatal but treatable disorder. We used electrospray tandem mass spectrometry in the New South Wales (Australia) Newborn Screening Programme to measure free carnitine and acylcarnitine species in the newborn population. Free carnitine levels in dried blood samples from 149,000 neonates did not vary markedly between 2 and 8 days of age. Two of 4 babies subsequently diagnosed clinically with the carnitine transporter defect had a free carnitine level in the neonatal blood sample low enough to be detected by screening.
Assuntos
Carnitina/análogos & derivados , Carnitina/deficiência , Proteínas de Transporte/genética , Proteínas de Transporte de Cátions Orgânicos , Espectrometria de Massas por Ionização por Electrospray , Peso ao Nascer , Carnitina/sangue , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Membro 5 da Família 22 de Carreadores de SolutoRESUMO
BACKGROUND: Newborn screening for cystic fibrosis (CF) with immunoreactive trypsinogen (IRT) and DeltaF508 analysis followed by sweat testing misses some infants with CF and detects more DeltaF508 carriers than expected. Some of the apparent DeltaF508 carriers may be DeltaF508 compound heterozygotes with normal sweat electrolyte levels. METHODS: Infants identified by newborn screening with an elevated IRT level, one DeltaF508 allele, and a sweat chloride level <60 mmol/L underwent CF mutation analysis, pancreatic stimulation testing, and repeat IRT analysis followed by clinical review and repeat sweat test at 12 months. RESULTS: Over a 24-month period we identified 122 DeltaF508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Three had clinical CF at 12 months (initial sweat chloride levels: 53, 51, and 32 mmol/L). Pancreatic electrolyte secretion in the subjects with a borderline sweat chloride level was similar to that in patients with known CF. CONCLUSION: The excess of DeltaF508 heterozygotes detected by IRT/DNA screening is associated with the presence of a second mutation or the 5T allele in some infants. Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype DeltaF508/R117H and DeltaF508/5T is required to determine their outcome. In the meantime, newborn screening should be confined to severe mutations associated with classic CF.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Testes de Função Pancreática , Fibrose Cística/metabolismo , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Tripsinogênio/metabolismo , Equilíbrio HidroeletrolíticoRESUMO
OBJECTIVES: To review the overall performance of a neonatal screening program for cystic fibrosis (CF) from 1981 to 1994, and to compare two strategies of case detection. PROGRAM DESIGN: Initially, immunoreactive trypsin (IRT) was measured in dried blood spots, and because of the low sensitivity of this test at days 3 to 5, a second sample was needed from babies with positive test results. Since 1993 a positive IRT assay result has been followed by direct gene analysis for the common CF mutation, delta F508, with the use of the same sample. Cases with false-negative results were actively sought throughout the period. RESULTS: With IRT alone, 1,015,000 babies were tested. Of 389 babies with CF, 30 had a clinical diagnosis of CF made after a negative screening test result or an administrative error. Early diagnosis was achieved in 92%. With the IRT/DNA protocol, 59 of 62 infants had a positive screening test result (44 were homozygous for delta F508) among 189,000 babies tested. Three babies with CF had no copy of this mutation, but two were identified early because of meconium ileus. The false-positive rate was much greater for IRT alone than for the IRT/DNA test (0.69% vs 0.054%). All false-positive cases in the IRT/DNA protocol were, of necessity, CF carriers. CONCLUSION: The percentage of babies with CF who had an early diagnosis was similar with the two protocols, but we concluded that the advantages of the IRT/DNA test for screening, particularly in the avoidance of the need for second IRT samples, outweighed the drawback of unwanted carrier detection.
Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal , Austrália/epidemiologia , Protocolos Clínicos , Fibrose Cística/epidemiologia , Fibrose Cística/genética , Sondas de DNA , Triagem de Portadores Genéticos , Homozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Mutagênese , Triagem Neonatal/economia , Mutação Puntual , Prognóstico , Estudos Retrospectivos , Tripsina/sangueRESUMO
A female neonate was seen because of shock, ketosis, and undetectable blood glucose. Initial urinary findings indicated the possibility of a defect of fatty acid beta-oxidation; subsequent studies showed that she had medium-chain acyl-coenzyme. A dehydrogenase deficiency. This case highlights the fact that the initial symptoms may occur in the first few days of life, and that the presence of ketosis does not exclude the possibility of a fatty acid oxidation defect; the profiles of urinary organic acids and acylglycines may not be characteristic at that time.
Assuntos
Ácidos Graxos Dessaturases/deficiência , Acil-CoA Desidrogenase , Glicemia/análise , Carnitina/sangue , Ácidos Graxos/urina , Feminino , Humanos , Recém-Nascido , Cetose/diagnóstico , Cetose/urina , Oxirredução , Fenobarbital/administração & dosagem , Fenobarbital/uso terapêuticoRESUMO
A term neonate became lethargic and hypotonic at 46 hours of age and died 10 hours later despite supportive therapy. Urinary organic acids indicated medium-chain acyl-coenzyme A dehydrogenase deficiency, and DNA studies confirmed this disorder. Neonatal symptoms in this enzyme deficiency have rarely been reported, and recent reviews have ignored or discounted this presentation.
Assuntos
DNA/genética , Ácidos Graxos Dessaturases/deficiência , Erros Inatos do Metabolismo Lipídico/metabolismo , Acil-CoA Desidrogenase , Ácidos Graxos Dessaturases/análise , Ácidos Graxos Dessaturases/genética , Ácidos Graxos/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Mutação , Reação em Cadeia da Polimerase , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Seventy-five thousand 5-day-old babies were screened for cystic fibrosis by blood spot immunoreactive trypsin (IRT) assay as part of a statewide screening program. IRT was elevated in 433 babies; retesting revealed persistent elevation in 38. Sweat testing confirmed cystic fibrosis in 35 babies and was normal in two babies, whose IRT remained elevated at the time of the test. Sweat testing was refused by one mother. Of the 35 babies with cystic fibrosis, 13 had meconium ileus or an already diagnosed affected sibling, but the diagnosis was unsuspected in 22, although all but four had some symptoms suggestive of cystic fibrosis. Stool trypsin activity at the time of the diagnostic screen was normal in nine and reduced in seven of the babies with cystic fibrosis. One baby did not have elevated IRT, and the cystic fibrosis was missed by the screening test. In a retrospective study of blood spot samples from 36 newborn infants, who were later diagnosed as having cystic fibrosis, all had IRT levels greater than in matched controls. Our study confirms that elevated IRT is characteristic of newborn babies with cystic fibrosis, and shows that this test is very specific and sensitive when used as a newborn screening test.
Assuntos
Fibrose Cística/sangue , Programas de Rastreamento , Tripsina/sangue , Austrália , Fibrose Cística/epidemiologia , Fezes/análise , Humanos , Recém-Nascido , Estudos Prospectivos , Tripsina/análiseRESUMO
One million 6-week-old infants were screened for aminoacidurias and the long-term follow-up analyzed to assess the benefits of the screening program. Apart from phenylketonuria, now normally detected by blood screening at five days, the most frequent abnormalities identified were cystinuria, histidinemia, Hartnup disease, and iminoglycinuria. Other disorders occurred less frequently than 1:100,000. Early diagnosis provided unequivocal clinical benefit only for phenylketonuria. There was probable benefit to patients with cystinuria, homocystinuria, argininosuccinic aciduria, and to some patients with Hartnup disease. However, benefit of early diagnosis in these disorders, of which the combined incidence was 1:10,000, was not clear-cut; for example, in 68 cystinuric children, four had already developed renal stones despite close medical supervision and a regimen of increased fluid intake to the limits of tolerance. No patient detected with any other condition benefited, either because the condition appeared benign and was not treated, or because the disorder was serious or lethal and there was a bad outcome despite early diagnosis and treatment. Existing urine screening programs should explore the incidence and clinical significance of further biochemical abnormalities detectable in the newborn infant, but there is no indication at present for the initiation of new urine screening programs designed to detect only aminoacidurias.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/prevenção & controle , Programas de Rastreamento , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Austrália , Cistinúria/prevenção & controle , Seguimentos , Histidina/urina , Humanos , LactenteRESUMO
Sisters aged 3 and 4 1/2 years, respectively, who had grown and developed normally were found to have methylmalonic aciduria. The elder had had only one previous illness, at 18 months, and was thriving at six years without treatment; she was excreting up to 2 gm methylmalonic acid per day. The younger sister died during her third episode of illness, at 3 years of age. Studies of cultured skin fibroblasts showed deficient methylmalonyl coenzyme A mutase apoenzyme activity; cobalamin metabolism was normal. There was a moderate response in cultured cells to large amounts of added hydroxycobalamin; but treatment of the patient with high doses of intramuscular vitamin B12 for ten days failed to lower the urinary excretion of methylmalonic acid.