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Veronica Wiley

Publications and source records attributed to Veronica Wiley.

15 recordsLinked to original sources
PubMed2007

Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study.

BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the disorder thought most to justify neonatal screening by tandem-mass spectrometry because, without screening, there seems to be substantial morbidity and mortality. Our aim was to assess the overall effectiveness of neonatal screening for MCAD deficiency in Australia. METHODS: We identified MCAD-deficient patients from a total population of 2,495,000 Australian neonates (810,000 screened) born between April 1, 1994, and March 31, 2004. Those from a cohort of 1,995,000 (460,000 screened) were followed up for at least 4 years, and we recorded number of deaths and severe episodes, medical and neuropsychological outcome, and hospital admissions within the screened and unscreened groups. FINDINGS: In cohorts aged at least 4 years there were 35 MCAD-deficient patients in those not screened (2.28 per 100,000 total population) and 24 in the screened population (5.2 per 100,000). We estimated that patients with this disorder in the unscreened cohort remained undiagnosed. Before 4 years of age, three screened patients had an episode of severe decompensation (including one neonatal death) versus 23 unscreened patients (including five deaths). At the most conservative estimate, relative risk of an adverse event was 0.44 (95% CI 0.13-1.45). In the larger cohort the relative risk (screened vs unscreened) of an adverse event by age 2 years was 0.26 (95% CI 0.07-0.97), also a conservative estimate. 38 of 52 living patients had neuropsychological testing, with no suggestions of significant differences in general cognitive outcome between the groups. INTERPRETATION: Screening is effective in patients with MCAD deficiency since early diagnosis reduces deaths and severe adverse events in children up to the age of 4 years.

Acyl-CoA Dehydrogenase↗
PubMed2006

Iodine status in pregnant women and their newborns: are our babies at risk of iodine deficiency?

OBJECTIVES: To determine whether pregnant women and their newborns show evidence of iodine deficiency, and to examine the correlation between maternal urine iodine concentration (UIC) and newborn thyroid-stimulating hormone (TSH) level. DESIGN: A cross-sectional study. SETTING: Hospital antenatal care services (March-May 2004) and private obstetrician clinics (June 2004) in the Central Coast area of New South Wales. PARTICIPANTS: 815 pregnant women (> or = 28 weeks' gestation) and 824 newborns. MAIN OUTCOME MEASURES: World Health Organization/International Council for the Control of Iodine Deficiency Disorders criteria for assessing severity of iodine deficiency (recommended levels: < 20% of urine samples in a population with UIC < 50 microg/L; and < 3% of newborns with whole-blood TSH level > 5 mIU/L). RESULTS: The median UIC for pregnant women was 85 microg/L, indicating mild iodine deficiency. Almost 17% of pregnant women had a UIC < 50 microg/L, and 18 newborns (2.2%) had TSH values > 5 mIU/L. There was no statistically significant linear correlation between neonatal whole-blood TSH level and maternal UIC (r = - 0.03; P = 0.4). Mothers with a UIC < 50 microg/L were 2.6 times (relative risk = 2.65; 95% CI, 1.49-4.73; P = 0.01) more likely to have a baby with a TSH level > 5 mIU/L. CONCLUSION: The pregnant women surveyed were mildly iodine deficient. TSH values for their newborns were mostly within acceptable limits. Ongoing surveillance of the iodine status of NSW communities to establish trends over time is recommended.

Adult↗
PubMed2005

Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.

The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.

Acyl-CoA Dehydrogenase↗
PubMed2005

Neonatal thyrotropin as measured in a congenital hypothyroidism screening program: influence of the mode of delivery.

CONTEXT: Many developed countries are reexperiencing iodine deficiency. One World Health Organization index of iodine deficiency in populations is the percentage of neonates with TSH levels greater than 5 mIU/liter 72 h after delivery. Measured TSH levels vary with methodology and are influenced by external factors including iodine exposure at time of delivery. OBJECTIVE: We wished to determine whether babies delivered by cesarean section have higher levels of TSH than babies delivered vaginally because this factor could influence determination of iodine deficiency. DESIGN AND SETTING: This was a cohort study of mothers delivering at a teaching hospital in 2002-2003 and their babies. PATIENTS AND METHODS: Women delivering a live infant were eligible for the study. Demographic data, mode of delivery, and subsequent routine newborn screening TSH levels were recorded. RESULTS: Of 2031 infants, 31.2% were delivered by cesarean section; 1864 babies were born after 37 wk, with blood samples collected by d 5 (>91% on d 3). Significant predictors of TSH concentration were the day TSH was measured and type of delivery. The distribution curve of TSH values was right shifted in infants born by cesarean section. The percentage of neonates born by cesarean with at TSH value greater than 5 was 7.1%. The figure for those born vaginally was 4.3%. CONCLUSIONS: Babies delivered by cesarean section are significantly more likely to have TSH levels greater than 5 mIU/liter on d 3 than those delivered vaginally. With the rise in the rate of births by cesarean, this could be an important factor in assessing population iodine deficiency using neonatal TSH levels.

Cesarean Section↗
PubMed2005

Tetrahydrobiopterin-responsive phenylketonuria: the New South Wales experience.

Recent studies have shown that a subgroup of phenylketonuric patients respond to high doses of BH4 (20 mg/kg) by a decrease of plasma phenylalanine. A clinically significant response has been defined as a decrease in phenylalanine by more than 30% within 24 h, after a BH4 challenge. We report our experience with 37 patients diagnosed with hyperphenylalaninemia, mild, moderate, or classical Phenylketonuria (PKU) using a seven day combined BH4 and phenylalanine load. Nine of the 37 patients responded with a 30% decrease in their phenylalanine levels in the first 8 h of treatment. A total of 17 patients (46%) had a decrease of at least 30% during the study period. This study confirms that a significant number of patients with mild to moderate PKU will respond to a BH4 load. Furthermore, it confirms that the seven-day phenylalanine test is more sensitive in detecting BH4 responsive patients.

Adolescent↗
PubMed2003

Screening newborns for inborn errors of metabolism by tandem mass spectrometry.

BACKGROUND: The recent development of electrospray tandem mass spectrometry makes it possible to screen newborns for many rare inborn errors of metabolism, but the efficacy and outcomes of screening remain unknown. We examined the effect of the screening of newborns by tandem mass spectrometry on the rates of diagnosis of 31 disorders. METHODS: We compared the rates of detection of 31 inborn errors affecting the metabolism of the urea cycle, amino acids, and organic acids and fatty-acid oxidation among 362,000 newborns screened by tandem mass spectrometry over a four-year period (April 1998 through March 2002) with the rates in six preceding four-year birth cohorts in New South Wales and the Australian Capital Territory, Australia, where screening, diagnostic, and clinical services were centralized. RESULTS: The overall prevalence of disorders during the periods when clinical diagnosis was used did not vary between 1982 and 1998. In the cohort screened with tandem mass spectrometry, the prevalence of inborn errors, excluding phenylketonuria, was 15.7 per 100,000 births (95 percent confidence interval, 11.9 to 20.4), as compared with adjusted rates of 8.6 to 9.5 per 100,000 births in the four preceding four-year cohorts. Of the 57 cases diagnosed after the introduction of newborn screening, 15 were diagnosed clinically; 7 of the 15 newborns had a normal result on screening. The rate of detection was increased specifically for medium-chain acyl-coenzyme A dehydrogenase deficiency (P<0.001) and other disorders of fatty-acid oxidation (P=0.007), as compared with the 16-year period before the implementation of neonatal screening for these disorders. CONCLUSIONS: More cases of inborn errors of metabolism are diagnosed by screening with tandem mass spectrometry than are diagnosed clinically. It is not yet clear which patients with disorders diagnosed by such screening would have become symptomatic if screening had not been performed.

Australian Capital Territory↗
PubMed2003

Newborn screening methods for cystic fibrosis.

An efficient newborn screening test for detecting cystic fibrosis has been available for over 20 years but is only now coming into widespread use. Blood immunoreactive trypsin is elevated in babies with cystic fibrosis and its measurement in dried blood spots is the primary screening tool. Poor discrimination in the first week requires a re-sampling step. The identification of the cystic fibrosis transmembrane conductance regulator gene and the discovery of a common mutation has allowed a combination of the primary screening test with a DNA test using the same sample. Differing genetic backgrounds have led to the development of population-specific protocols. A false-negative rate of around 5% is usual. Specificity is high. In all protocols involving a DNA test, confirmation of the diagnosis by sweat test is necessary when only one mutation is identified, identification of some carriers therefore being unavoidable. Careful counselling is needed for the families of these carriers.

Cystic Fibrosis↗
PubMed2003

Postpartum maternal iodine status and the relationship to neonatal thyroid function.

Iodine deficiency in the postpartum period has the potential to affect neonatal neuropsychointellectual development. We performed a cross-sectional study involving 50 postpartum women and their neonates, measuring maternal urine iodine, breast milk iodine, and neonatal thyroid stimulating hormone (TSH), and examining their interrelationships. Women were studied at a median (range) of 4 (3-9) days postpartum. Moderate to severe iodine deficiency (defined by urine iodine concentration < 50 microg/L) was found in 29 of the 50 subjects (58%). The median +/- standard deviation (SD) urine iodine was 46.8 +/- 28.5 microg/L and the mean urine iodine expressed in micrograms per gram of creatinine was 86.6 +/- 45.6. The median (range) breast milk iodine was 84.0 microg/L (25.0-234.0). Breast milk iodine was significantly correlated with urine iodine in micrograms per gram of creatinine (r = 0.52, p < 0.001) but not with urine iodine measured in micrograms per liter (r = 0.19, p = 0.2). Six percent of neonates had whole-blood TSH values of greater than 5 mIU/L. Neonatal TSH levels were positively correlated with higher breast milk iodine (r = 0.42, p = 0.003). There was no significant correlation between neonatal TSH levels and the mother's urine iodine content. There is a high prevalence of iodine deficiency in these lactating postpartum subjects. Urine iodine as micrograms per gram of creatinine is a good predictor of breast milk iodine content. In our study, higher breast milk iodine was correlated with a higher neonatal TSH. The impact of breast milk iodine content on neonatal TSH levels and neuropsychointellectual development needs further study.

Adult↗
PubMed2003

Information overload--new technologies, can we store the data?

Computerization within newborn screening programs is a developing issue. To date two basic approaches to data storage have been used: (1) a storage system for babies diagnosed with a disorder, (2) a comprehensive system with long-term details for all patient samples, tests performed, test results and interpretations. It usually provides efficient real-time reports for various clinical and quality control requirements and easy access to an inborn errors registry. Within the last decade there have been two new technologies adapted to routine use in newborn screening laboratories: (1) tandem mass spectrometry for selected amino acids and acyl carnitine, and (2) DNA mutational analysis of PCR products. Both technologies present data storage challenges. Both are capable of providing large files of information for a sample. Consideration must be given to how these data are stored, whether all results including a graphical representation or DNA sequence data are kept or whether only final results for specific analytes are stored. Many new analytical technologies can only be incorporated into routine programs as a result of advances in hardware and software allowing better access to, and storage of, data.

Australia↗
PubMed2003

Newborn screening--is it really that simple?

The incorporation of tandem mass spectrometry (MSMS) into an existing newborn screening program is an evolving process. Limited worldwide experience has ensured that all stages of reliability testing need to be followed. These include a literature review to establish methodology and analytes/disorders for testing and a pilot screening project including assaying archival samples from subjects with proven target disorders. Algorithms used for analyte concentrations and the relationships of various analytes to one another for resample criteria need to be continually reassessed to maximise screening specificity, sensitivity and positive predictive value. Since 1st of April 1998, the NSW Newborn Screening Program has screened 320, 848 babies using electrospray MSMS for selected amino acids and acyl camitines. Screening for amino acids has led to requests for 415 repeat samples with 94 babies referred for further testing. Of these 73 had a disorder of amino acid metabolism, including 43 with persistent hyperphenylalaninemia (36 of whom had PKU, 2 had a pterin pathway defect, 5 HPAA). Screening for acyl carnitines has led to requests for 245 repeat samples with 63 babies referred for further investigation. Of these 44 had a diagnosed disorder, including 15 with medium chain acyl CoA dehydrogenase deficiency. Five babies with confirmed disorders detectable with MS/MS had negative test results. The cost of screening using MSMS was only $A0.50 more than the method for screening for PKU and homocystinuria alone (ie the bacterial inhibition assays) and has allowed detection of an additional 74 babies at least 48 of whom have a diagnosis for which early treatment seems clearly beneficial. MSMS has shown a sensitivity of 95.9% and specificity of 99.8% in our laboratory with a positive predictive value of 18%.

Acyl-CoA Dehydrogenase↗
PubMed2002

Neonatal thyroid-stimulating hormone concentrations in northern Sydney: further indications of mild iodine deficiency?

OBJECTIVE: To determine whether thyroid-stimulating hormone (TSH) concentrations in a large sample of neonates meet World Health Organization criteria for an iodine-replete population (< 3% of neonates with whole-blood TSH concentrations > 5 mlU/L), and, in a small subset of neonates, to examine the correlation between maternal urinary iodine and neonatal TSH concentrations. DESIGN: Cross-sectional study of neonatal whole-blood TSH values obtained as part of a routine newborn screening program. SETTING: Royal North Shore Hospital (RNSH) in northern Sydney. PARTICIPANTS: Two anonymous samples of neonates born at RNSH (1316 infants born between August 1998 and April 1999 and 1457 infants born between 1 March and 31 December 2000); and 84 infants whose mothers had attended RNSH between September 1998 and August 1999 and supplied a urine sample for iodine measurement. MAIN OUTCOME MEASURES: Iodine status of neonates (proportion with whole-blood TSH values > 5 mlU/L), and urine iodine concentrations of pregnant women. RESULTS: In the two large population samples of neonates, 8.1% (95% CI, 6.6%-9.5%) and 5.4% (95% Cl, 4.3%-6.6%), respectively, had whole-blood TSH values > 5 mlU/L (prevalence range for mild thyroid deficiency, 3%-19%). Comparing the TSH values of the 1316 anonymous infants and the 84 identified infants showed no difference between the proportions with TSH values > 5 mlU/L (8.1% v 10.7%, respectively; P = 0.39). Urine iodine concentrations in the 84 pregnant women indicated borderline mild iodine deficiency. TSH values in their 84 infants were positively correlated with maternal urine iodine concentrations. CONCLUSIONS: Our results suggest that the population of northern Sydney may have mild iodine deficiency. However, the expected relationship between maternal urine iodine levels and neonatal TSH concentrations was not found.

Congenital Hypothyroidism↗
PubMed2002

Application of tandem mass spectrometry to biochemical genetics and newborn screening.

Tandem mass spectrometry (MS/MS) has become a key technology in the fields of biochemical genetics and newborn screening. The development of electrospray ionisation (ESI) and associated automation of sample handling and data manipulation have allowed the introduction of expanded newborn screening for disorders which feature accumulation of acylcarnitines and certain amino acids in a number of programs worldwide. In addition, the technique has proven valuable in several areas of biochemical genetics including quantification of carnitine and acylcarnitines, in vitro studies of metabolic pathways (in particular beta-oxidation), and diagnosis of peroxisomal and lysosomal disorders. This review covers some of the basic theory of MS/MS and focuses on the practical application of the technique in these two interrelated areas.

Amino Acids↗
PubMed2002

Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962.

Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.

Animals↗