Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Carnitine O-Palmitoyltransferase/genetics , Codon, Nonsense , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Chromosomes, Human, Pair 1/genetics , Fatal Outcome , Humans , Infant, Newborn , Male , Multicystic Dysplastic Kidney/diagnosis , Multicystic Dysplastic Kidney/genetics , Multicystic Dysplastic Kidney/pathologySubject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/diagnosis , Genetic Testing/methods , Mutation , Neonatal Screening/methods , Sweat/chemistry , Chlorides/analysis , Chlorides/metabolism , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Electric Conductivity , Female , Heterozygote , Homozygote , Humans , Infant, Newborn , Scotland , Sequence Analysis, DNA , Sodium/analysis , Sodium/metabolism , Sweating , Trypsin/analysis , Trypsin/immunologyABSTRACT
Neonatal jaundice is common, and usually harmless, because of physiological jaundice or breast-feeding. In some neonates unconjugated bilirubin concentration, coupled with other risk factors, is sufficient to allow free bilirubin to cross the blood-brain barrier and cause kernicterus. Another subgroup of infants is jaundiced because of elevated conjugated bilirubin; a marker for a number of pathological conditions. Bilirubin measurement must identify those infants at risk. Transcutaneous bilirubin measurement is increasingly used in healthy infants, especially before early discharge or at home, to assess the need for laboratory bilirubin measurement. Transcutaneous measurements are not covered by laboratory quality assessment schemes. Guidelines on management of neonatal jaundice utilize age in hours and other risk factors to define bilirubin action thresholds, which may be as low as 100 micromol/L for sick premature infants, whereas early discharged babies may only present after bilirubin concentrations are extremely high. Hence, there is a requirement for accurate total bilirubin measurement from <100 to >500 micromol/L, with sufficient precision to assess the rate of bilirubin change with time. Babies presenting with late jaundice always require conjugated bilirubin measurement. It is of concern that many total and direct bilirubin automated kit methods suffer from haemolysis interference, while use of in-house methods or modification of commercial methods has virtually disappeared. External quality assessment has a vital role in providing data on different methods' performance, including accuracy, precision and susceptibility to interference. Laboratories should consider whether their adult bilirubin methods are suitable for neonates.
Subject(s)
Chemistry, Clinical/methods , Jaundice, Neonatal/blood , Jaundice, Neonatal/diagnosis , Animals , Bilirubin/chemistry , Heme/chemistry , Humans , Infant, Newborn , Kernicterus/blood , Kernicterus/diagnosis , Models, Chemical , Quality Control , Rats , Reproducibility of Results , Risk FactorsABSTRACT
Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may present with variable neurological manifestations. Radiological features include white matter changes (leukoencephalopathy). Clinical, biochemical, and radiological response to treatment may again be variable. Here we present a 12-year follow-up of two siblings on the same treatment regimen, with contrasting long-term findings. The first patient, a female presenting at 15 years, showed a good clinical response, substantial intellectual gain, and complete reversal of leukoencephalopathy. Her brother presented at 13 years 9 months and showed limited clinical and cognitive improvement with persistence of the leukoencephalopathy. Both siblings showed a partial biochemical response to treatment.
Subject(s)
Folic Acid/therapeutic use , Homocystinuria/drug therapy , Intelligence/drug effects , Leukoencephalopathy, Progressive Multifocal/drug therapy , Methylenetetrahydrofolate Reductase (NADPH2)/deficiency , Activities of Daily Living/classification , Adolescent , Adult , Betaine/therapeutic use , Brain/drug effects , Brain/pathology , Drug Therapy, Combination , Female , Follow-Up Studies , Homocystinuria/diagnosis , Homocystinuria/genetics , Humans , Leukoencephalopathy, Progressive Multifocal/diagnosis , Long-Term Care , Magnetic Resonance Imaging , Male , Methionine/blood , Neurologic Examination/drug effects , Treatment OutcomeABSTRACT
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterized by thymine-uraciluria in homozygous deficient patients. Cancer patients with a partial deficiency of DPD are at risk of developing severe life-threatening toxicities after the administration of 5-fluorouracil. Thus, identification of novel disease-causing mutations is of the utmost importance to allow screening of patients at risk. In eight patients presenting with a complete DPD deficiency, a considerable variation in the clinical presentation was noted. Whereas motor retardation was observed in all patients, no patients presented with convulsive disorders. In this group of patients, nine novel mutations were identified including one deletion of two nucleotides [1039-1042delTG] and eight missense mutations. Analysis of the crystal structure of pig DPD suggested that five out of eight amino acid exchanges present in these patients with a complete DPD deficiency, Pro86Leu, Ser201Arg, Ser492Leu, Asp949Val and His978Arg, interfered directly or indirectly with cofactor binding or electron transport. Furthermore, the mutations Ile560Ser and Tyr211Cys most likely affected the structural integrity of the DPD protein. Only the effect of the Ile370Val and a previously identified Cys29Arg mutation could not be readily explained by analysis of the three-dimensional structure of the DPD enzyme, suggesting that at least the latter might be a common polymorphism. Our data demonstrate for the first time the possible consequences of missense mutations in the DPD gene on the function and stability of the DPD enzyme.
