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Bridget Wilcken

Publications and source records attributed to Bridget Wilcken.

At least 19 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↗
PubMed2007

Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.

Africa↗
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↗
PubMed2006

Asymmetric dimethylarginine in homocystinuria due to cystathionine beta-synthase deficiency: relevance of renal function.

OBJECTIVE: Vascular disease is associated with increased plasma asymmetric dimethylarginine (ADMA) and homocysteine, and both are increased in renal failure. In cystathionine beta-synthase deficiency (CBS) there is severe hyperhomocysteinaemia, precocious vascular disease, and endothelial dysfunction. We investigated whether ADMA levels are elevated in CBS patients with and without renal impairment, and whether lowering plasma homocysteine also lowers ADMA. METHODS: We measured plasma homocysteine, arginine, asymmetric and symmetric dimethylarginines, nitrate + nitrite, creatinine and cystatin C in 23 CBS-deficient patients and 24 age-matched controls. RESULTS: In the patients, nitrate + nitrite and the ratio L: -arginine/ADMA were markedly reduced (21.6 +/- 6.1 vs 57.7 +/- 7.5 micromol/L and 132.9 +/- 24.7 vs 181.9 +/- 56.1, respectively, p < 0.001 for both), reflecting endothelial dysfunction. Plasma ADMA for the group was moderately increased (0.55 +/- 0.08 vs 0.49 +/- 0.07 micromol/L, p = 0.018), but this was due to significantly higher levels than controls in only those 7 of the 23 patients who had elevated cystatin C levels (0.59 +/- 0.08 vs 0.49 +/- 0.07 mg/L, p = 0.007). Posttreatment total homocysteine in patients varied widely (15-285, median 92 micromol/L), but was not correlated with ADMA or other measured variables. In three newly-diagnosed patients, marked reduction of total homocysteine during treatment produced minimal changes in ADMA. CONCLUSIONS: ADMA levels were significantly increased only in the CBS-deficient patients with elevated cystatin C levels, and not in those with normal renal function. The reported relationship between hyperhomocysteinaemia and ADMA may not be direct, but could be secondary to reduced renal function.

Adult↗
PubMed2006

Abnormal glycosylation with hypersialylated O-glycans in patients with Sialuria.

Sialuria is an inborn error of metabolism characterized by coarse face, hepatomegaly and recurrent respiratory tract infections. The genetic defect in this disorder results in a loss of feedback control of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase by CMP-N-acetylneuraminic acid (CMP-NeuAc) resulting in a substantial overproduction of cytoplasmic free sialic acid. This study addresses fibroblast CMP-NeuAc levels and N- and O-glycan sialylation of serum proteins from Sialuria patients. CMP-NeuAc levels were measured with HPLC in fibroblasts. Isoelectric focusing (IEF) of serum transferrin and of apolipoprotein C-III (apoC-III) was performed on serum of three Sialuria patients. Isoforms of these proteins can be used as specific markers for the biosynthesis of N- and core 1 O-glycans. Furthermore, total N- and O-linked glycans from serum proteins were analyzed by HPLC. HPLC showed a clear overproduction of CMP-NeuAc in fibroblasts of a Sialuria patient. Minor changes were found for serum N-glycans and hypersialylation was found for core 1 O-glycans on serum apoC-III and on total serum O-glycans in Sialuria patients. HPLC showed an increased ratio of disialylated over monosialylated core 1 O-glycans. The hypersialylation of core 1 O-glycans is due to the increase of NeuAcalpha2,6-containing structures (mainly NeuAcalpha2-3Galbeta1-3[NeuAcalpha2-6]GalNAc). This may relate to KM differences between GalNAc-alpha2,6-sialyltransferase and alpha2,3-sialyltransferases. This is the first study demonstrating that the genetic defect in Sialuria results in a CMP-NeuAc overproduction. Subsequently, increased amounts of alpha2,6-linked NeuAc were found on serum core 1 O-glycans from Sialuria patients. N-glycosylation of serum proteins seems largely unaffected. Sialuria is the first metabolic disorder presenting with hypersialylated O-glycans.

Apolipoprotein C-III↗
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↗
PubMed2005

Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene.

Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation resulting from defective carnitine transport. This disease is caused by mutations in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. Here we validate dye-binding/high-resolution thermal denaturation as a screening procedure to identify novel mutations in this gene. This procedure is based on the amplification of DNA by PCR in capillaries with the dsDNA binding dye LCGreen I. The PCR reaction is then analyzed in the same capillary by high-resolution thermal denaturation. Samples with abnormal melting profiles are sequenced. This technique correctly identified all known patients who were compound heterozygotes for different mutations in the carnitine transporter gene and about 30% of homozygous patients. The remaining 70% of homozygous patients were identified by a second amplification, in which the patient's DNA was mixed with the DNA of a normal control. This screening system correctly identified eight novel mutations and both abnormal alleles in six new families with primary carnitine deficiency. The causative role of the missense mutations identified (c.3G>T/p.M1I, c.695C>T/p.T232M, and c.1403 C>G/p.T468R) was confirmed by expression in Chinese hamster ovary (CHO) cells. These results expand the mutational spectrum in primary carnitine deficiency and indicate dye-binding/high-resolution thermal denaturation as an ideal system to screen for mutations in diseases with no prevalent molecular alteration.

Animals↗
PubMed2004

Perimortem laboratory investigation of genetic metabolic disorders.

Over 400 rare, biochemically diverse genetic metabolic disorders (inborn errors of metabolism) have been described and the list is growing by the month. Although recent advances in the diagnosis and treatment of these disorders have substantially improved the prognosis for many of them, including those presenting in the neonatal period, a proportion of affected individuals die before the diagnosis can be confirmed and, in some cases, before the diagnosis is even considered. This review will provide an outline of the range of clinical presentations seen in neonates with genetic metabolic disorders and provide a practical approach for rapid biochemical screening for these disorders. In addition, suggested guidelines are given for the collection of relevant samples in the perimortem period, the aim being to maximize the chance of identifying any underlying genetic metabolic disorder.

Autopsy↗
PubMed2004

Problems in the management of urea cycle disorders.

Several recent reviews describe the management of urea cycle disorders. There is much agreement on diet, alternative pathway therapy, maintenance of arginine and ornithine levels in acute and chronic management, sick-day regimens, and some aspects of monitoring. However, differences remain in several areas, and physicians at most treatment centers have relatively little experience, because these disorders are rare. Early suspicion of the diagnosis of a urea cycle disorder, and prompt referral to a tertiary center is vital. Drug treatment using chronic administration of sodium benzoate has been abandoned by some centers, but the acceptability of phenylbutyrate is an issue for many patients. Using citrulline chronically is not always successful in recommended doses, and may result in an arginine level too low for maximum control. Appetite and nutrition problems are common. One major concern is the early identification and management of chronic catabolism, theoretically easy, but hard in practice. Biochemical measurement problems complicate monitoring, and there are disagreements about the optimum way of identifying OTC carriers. It is not always clear whom to treat. Within a kindred with an early-onset phenotype, an asymptomatic newborn girl may need treatment for some undetermined time, but target values for monitoring are not clear. In late-onset phenotypes, management of asymptomatic males identified by family screening is also difficult. Most centers do not have sufficient cases to solve these conundrums, some of which require further multicenter study. This paper examines the recommendations of a consensus conference on management, outlines some remaining problems, and incorporates in the text the points raised in open discussion during a session of a symposium held in Sydney in 2003 entitled "New Developments in Urea Cycle Disorders."

Adult↗
PubMed2003

Ethical issues in newborn screening and the impact of new technologies.

Medical ethics is an integral part of medical practice. The general principles are well known: autonomy (the right to choose), beneficence (do good), non-maleficence (do no harm), and justice (be fair and equitable). In newborn screening these principles must be especially carefully applied, as the intervention, screening, has not been sought by the patient, but is a form of preventive medicine. In proposing a screening programme questions to be asked are: should we do it? (is there enough benefit, not too much harm?); can we do it? (do we have the technology and skill to find the cases sought); can we afford it? The first question, with its ethical implications, is often ignored. New issues have arisen with new technology, but underlying ethical themes are the same. Tandem mass spectrometry can be used to detect about 30 very rare disorders in a single test. Proving the benefit of this (and other screening tests) is difficult because randomised controlled trials seem impractical, because of power considerations, long follow-up time, and because there is already a perceived benefit. Best possible evidence of a lower order must be sought. In future, DNA microarray technology is likely to become sufficiently inexpensive to apply to newborn screening. It is difficult to predict all the future possibilities of DNA technology in this fast-moving field. Major ethical problems are likely with the ability to detect adult-onset disorders or susceptibility to these in babies. Under what circumstances would this be ethical? We need to start debating these issues.

Ethics, Medical↗
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

Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa.

Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case-control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's chi(2)=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (chi(2)=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism.

Anorexia Nervosa↗
PubMed2003

Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.

The conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity. Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene; most mutations are predicted to completely abolish protein function. Mutations identified include c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. Clinical severity of MGA1 in published patients has been quite variable. Included in the present study is an additional patient with MGA1 who was detected by neonatal screening and has remained asymptomatic up to his present age of 2 years. The boy is homozygous for an N-terminal frameshift mutation in the AUH gene. Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases. Further work is required to identify external or genetic factors associated with development of clinical problems in patients with MGA1.

Amino Acid Metabolism, Inborn Errors↗
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↗