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B Wilcken

Publications and source records attributed to B Wilcken.

At least 19 recordsLinked to original sources
PubMed2007

Non-ketotic hyperglycinemia is usually not detectable by tandem mass spectrometry newborn screening.

Diagnosis of Non-Ketotic Hyperglycinemia by MSMS newborn screening might benefit patients with post-neonatal presentation. We screened 733,527 babies over eight years, and nine babies were subsequently diagnosed with NKHG. Two had newborn glycine levels above our cut-off and presented within 72 h. The remaining patients could not have been diagnosed by newborn screening without an unacceptably high recall rate. We conclude that babies with NKHG are not usually identifiable by current newborn screening strategies.

Glycine↗
PubMed2007

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

Glutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography-mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L: -carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

Child↗
PubMed2006

Newborn screening may fail to identify intermediate forms of maple syrup urine disease.

The New South Wales state-wide newborn screening programme has offered comprehensive screening for inborn errors of metabolism, including MSUD, using electrospray tandem mass spectrometry since 1998. Over this period, a number of patients with classic MSUD have been identified with subsequent good neurological outcome. We describe two patients with an intermediate form of MSUD who presented later in childhood. Retrospective review of their newborn screening results demonstrates that the diagnosis could not have been made by current newborn screening. Their neurological outcome is much less satisfactory. Despite the usefulness of expanded newborn screening programmes in detecting severe neonatal presentations of inborn errors of metabolism, partial enzyme deficiencies may not be detected. Metabolic diseases still need to be considered in appropriate clinical situations later in life.

Alanine↗
PubMed2006

Selection of reference genes for quantitative real-time PCR analysis in canine mammary tumors using the GeNorm algorithm.

Eleven reference genes (18s ribosomal ribonucleic acid [RNA], 28s ribosomal RNA, ubiquitin, beta-actin, glycerine aldehyde dehydrogenase, ATP-synthase subunit 5B, hydroxymethyl-bilane synthase, hypoxanthine-phosphoribosyl transferase, ribosomal protein L32, tryptophan 5-monooxygenase activation protein (zeta polypeptide), and TATA-Box binding protein) were analyzed in use as references for gene expression profiling experiments using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in canine mammary tumors. The transcription level of the candidates was measured in 22 histologically characterized excised tumor specimens from mammary gland tissue and 22 samples of non-neoplastic mammary tissue samples from the same individuals. Results were used to rank candidate reference genes using the GeNorm tool. It was determined that in samples of canine mammary gland tissue, a combination of hypoxanthine-phosphoribosyl transferase, ATP-synthase subunit 5B, ribosomal protein L32 and ubiquitin yields stable reference gene expression levels, whereas the use of glycerin aldehyde dehydrogenase or ribosomal RNA is unsuitable for normalization of qRT-PCR results in this tissue type.

Algorithms↗
PubMed2002

3-Hydroxyglutarate excretion is increased in ketotic patients: implications for glutaryl-CoA dehydrogenase deficiency testing.

Three patients with ketosis had increased excretion of 3-hydroxyglutarate (21.8-37.9 micromol/mmol creatinine; controls 2.3 +/- 1.6), an indicator of glutaryl-CoA dehydrogenase deficiency (GDHD), which normalized when the patients were nonketotic. Clinical assessment of all three patients and enzyme studies in one patient were not consistent with GDHD. These findings were compared with those of other ketotic patients, who showed statistically significant increases in 3-hydroxyglutarate excretion (9.4 +/- 5.0 micromol/mmol creatinine; p < 0.01), and with those of a child with confirmed GDHD when she was both ketotic and nonketotic. Secondary increase in 3-hydroxyglutarate excretion during ketosis is a potential confounder in the diagnosis of GDHD.

Child, Preschool↗
PubMed2002

Hartnup disorder: polymorphisms identified in the neutral amino acid transporter SLC1A5.

Hartnup disorder is an inborn error of renal and gastrointestinal neutral amino acid transport. The cloning and functional characterization of the 'system B0' neutral amino acid transporter SLC1A5 led to it being proposed as a candidate gene for Hartnup disorder. Linkage analysis performed at 19q13.3, the chromosomal position of SLC1A5, was suggestive of an association with the Hartnup phenotype in some families. However, SLC1A5 was not linked to the Hartnup phenotype in other families. Linkage analysis also excluded an alternative candidate region at 11q13 implicated by a putative mouse model for Hartnup disorder. Sequencing of the coding region of SLC1A5 in Hartnup patients revealed two coding region polymorphisms. These mutations did not alter the predicted amino acid sequence of SLC1A5 and were considered unlikely to play a role in Hartnup disorder. There were no mutations in splice sites flanking each exon. Quantitative RT-PCR of SLC1A5 messenger RNA in affected and unaffected subjects did not support systemic differences in expression as an explanation for Hartnup disorder. In the six unrelated Hartnup pedigrees studied, examination of linkage at 19q13.3, polymorphisms in the coding sequence and quantitation of expression of SLC1A5 did not suffice to explain the defect in neutral amino acid transport.

Amino Acid Transport System ASC↗
PubMed2002

Anorexia nervosa (restrictive subtype) is associated with a polymorphism in the novel norepinephrine transporter gene promoter polymorphic region.

Long-term weight-restored patients with anorexia nervosa (AN) have lower norepinephrine levels than controls. Since this may reflect altered reuptake by the norepinephrine transporter (NET), we hypothesised that the NET gene was involved in the genetic component of AN. PCR-amplification of an AAGG repeat island (AAGG1) in the NET gene promoter region revealed a novel 343-bp sequence with five additional AAGG repeat islands (AAGG2-AAGG6). We named the sequence from AAGG1 to AAGG6 inclusive, the NET gene promoter polymorphic region (NETpPR). A 4-bp deletion (S4) or insertion (L4) in AAGG4 resulted in the net loss or gain, respectively, of a putative Elk-1 transcription factor site. The transmission disequilibrium test(TDT) with 87 Australian trios (patient plus parents) demonstrated significant preferential transmission of L4 (McNemar's chi(2) = 7.806, df = 1, P = 0.0052, odds ratio: 2.1) from parent to child with restricting AN (AN-R), suggesting that L4 or a DNA variant in linkage disequilibrium with it, doubles the risk for developing AN-R.

Adolescent↗
PubMed2002

Clinical approach to inborn errors of metabolism presenting in the newborn period.

Inborn errors of metabolism are individually rare, but collectively are responsible for significant levels of paediatric morbidity and mortality. More than 400 biochemically diverse inborn errors of metabolism have been identified. Recent advances in the diagnosis and treatment of these disorders have substantially improved the prognosis for many of them. Paediatricians and neonatologists play a vital role in identifying which patients need to be investigated. The diagnosis of an inborn error of metabolism often needs to be established quickly in order to prevent death or permanent neurological sequelae, and this should be carried out in collaboration with a specialized unit. The present review provides a practical approach to the recognition and investigation of neonates in whom an inborn error may be present. We also provide guidelines for the stabilization and initial management of infants at high risk of a metabolic disorder.

Humans↗
PubMed2001

Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: increased accuracy employing DNA, enzyme, and metabolite analyses.

Inherited succinic semialdehyde dehydrogenase (SSADH; EC1.2.1.24; McKusick 271980) deficiency is a defect of GABA degradation which leads to accumulation of 4-hydroxybutyric acid (gamma-hydroxybutyric acid; GHB) in physiologic fluids of patients. Prenatal diagnosis (PND) was performed in three at-risk pregnancies employing combinations of: (1) reverse-transcription-polymerase chain reaction (RT-PCR) and genomic DNA amplification followed by sequencing using isolated leukocytes or cultured human lymphoblasts; (2) GHB quantitation in amniotic fluid; or (3) SSADH enzyme assay in chorionic villus (CV) and/or amniocytes. In two pregnancies, all analyses were concordant for prediction of disease status in the fetus. In the third case, enzyme activity in CV (deficient) and metabolite analysis in amniotic fluid (normal) were discordant. For clarification, mutation analysis was undertaken in CV, confirming heterozygosity for the mutation previously identified in the proband. We hypothesize that delayed transit time for shipment of CV between Greece and the United States (8 days) led to enhanced degradation of heterozygous SSADH enzyme activity. Our data demonstrate the importance of combined metabolite, enzyme, and DNA analysis for increased accuracy in the PND of SSADH deficiency.

Aldehyde Oxidoreductases↗
PubMed2001

Carnitine palmitoyltransferase I deficiency in neonate identified by dried blood spot free carnitine and acylcarnitine profile.

A neonate at risk for hepatic carnitine palmitoyltransferase I (L-CPT I) deficiency was investigated from birth. The free carnitine and acylcarnitine profile in dried whole blood filter paper samples collected at ages 1 and 4 days showed a markedly elevated concentration of free carnitine (141 and 142 micromol/L, respectively), normal concentrations of acetyl- and propionylcarnitine, with the near absence of all other species. The diagnosis was confirmed by in vitro fatty acid oxidation screening assays and enzyme assay in cultured skin fibroblasts. Retrospective study of the newborn whole blood sample of the index case showed a similar profile (free carnitine 181 micromol/L). The newborn population distribution of free carnitine (n = 143,981) showed that only three samples had free carnitine > 140 micromol/L (>99.9th centile), two were from L-CPT I-deficient neonates and one from a baby with sepsis. While there are other conditions that can cause elevated concentrations of free carnitine, an isolated elevation of free carnitine only in an apparently healthy term neonate warrants further investigation to exclude L-CPT I deficiency.

Carnitine↗
PubMed2001

Ornithine carbamoyltransferase deficiency: improved sensitivity of testing for protein tolerance in the diagnosis of heterozygotes.

The most direct test of functional capacity of the liver in nitrogen disposal is to stress the urea cycle with a high protein load. This has been used in the diagnosis of heterozygosity for ornithine carbamoyltransferase deficiency for many years by measuring the subsequent excretion of orotic acid in urine. Reports have shown some ambiguity in both this and the more recent allopurinol test. We investigated the effects of different foods as the protein load and of different analytical methods. A standardized protocol was developed, giving 35 g protein per m2 surface area as steamed fat-free chicken breast to be eaten within 30 min. Urine was collected at zero time and over 0-2, 2-4 and 4-6 h. Compliance was checked by assessing excretion of amino acids. Diagnostic sensitivity was improved by reference to the change in excretion, i.e. the ratio of excretions 2-4 h/0-2 h. Extension of the test to 6 h gave no diagnostic advantage over a 4 h test. Comparison of the analysis of total orotic acids by the photometric method of Harris and Oberholtzer, the reference method for this study, with that by the method of Goldstein and colleagues showed that the latter gave erratic results with some false positives. However, comparison of the method of Harris and Oberholtzer with specific orotic acid analysis by a modification of the stable-isotope internal standard method of Rimoldi and colleagues yielded the same diagnoses. The improved protein load test gave a clearly positive result in all 16 obligate heterozygotes and 2 possible heterozygotes tested from 14 kindred, and a clearly negative result in all 18 control subjects and all 6 of the possible heterozygotes who were later shown by DNA studies not to carry the family mutation. The test appears at least as sensitive and specific as the allopurinol test, and is more convenient because of the short period of sample collection.

Adolescent↗
PubMed2001

Rare diseases and the assessment of intervention: what sorts of clinical trials can we use?

There is increasing emphasis on the importance of practising evidence-based medicine. Randomized controlled trials are the standard way to assess the benefits of an intervention, and observational studies are not usually accorded much weight; the results are likely to be considered misleading. For rare diseases, there are great difficulties in obtaining adequate evidence for interventions or for the benefits of early diagnosis. This is because the disorders are not only very rare but also have variable expression, may have very long courses, and have incompletely known late effects; and surrogate end-points often have to be used. Randomized controlled trials are usually impossible because of inadequate power, and because there are preconceived notions of the effects of treatments already in use. The adoption of the best possible design for observational trials, formation of a central registry of such trials, and a greater general appreciation of the problems that rare diseases pose will help in obtaining the best possible evidence for the effects of interventions.

Clinical Trials as Topic↗
PubMed2001

Carnitine transporter defect diagnosed by newborn screening with electrospray tandem mass spectrometry.

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.

Birth Weight↗
PubMed2001

Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275 000 babies.

OBJECTIVE: To evaluate newborn screening by tandem mass spectrometry for detection of medium chain acyl-CoA dehydrogenase (MCAD) deficiency, a fatty acid oxidation disorder with significant mortality in undiagnosed patients. DESIGN: The following were studied: (a) 13 clinically detected MCAD deficient subjects, most homozygous for the common A985G mutation, whose newborn screening sample was available; (b) 275 653 consecutive neonates undergoing routine newborn screening. Screened infants with blood octanoylcarnitine levels > or = 1 micromol/l were analysed for the A985G mutation, had analysis of plasma and repeat blood spot acylcarnitines and urinary organic acids, and had fibroblast fatty acid oxidation or acylcarnitine studies. RESULT: Twelve of the 13 patients later diagnosed clinically had newborn octanoylcarnitine levels > 2.3 micromol/l. Twenty three screened babies had initial octanoylcarnitine levels > or = 1 micromol/l. Eleven of 12 babies with persistent abnormalities had metabolite and/or enzyme studies indicating MCAD deficiency. Only four were homozygous for the A985G mutation, the remainder carrying one copy. CONCLUSIONS: Most patients with symptomatic MCAD deficiency could be detected by newborn screening. Infants actually detected had a lower frequency of A985G alleles than clinically diagnosed cases and may have a lower risk of becoming symptomatic.

Acyl-CoA Dehydrogenase↗
PubMed2001

Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study.

An inborn error of metabolism, homocystinuria due to cystathionine beta-synthase deficiency, results in markedly elevated levels of circulating homocysteine. Premature vascular events are the main life-threatening complication. Half of all untreated patients have a vascular event by 30 years of age. We performed a multicenter observational study to assess the effectiveness of long-term homocysteine-lowering treatment in reducing vascular risk in 158 patients. Vascular outcomes were analyzed and effectiveness of treatment in reducing vascular risk was evaluated by comparison of actual to predicted number of vascular events, with the use of historical controls from a landmark study of 629 untreated patients with cystathionine beta-synthase deficiency. The 158 patients had a mean (range) age of 29.4 (4.5 to 70) years; 57 (36%) were more than 30 years old, and 10 (6%) were older than 50 years. There were 2822 patient-years of treatment, with an average of 17.9 years per patient. Plasma homocysteine levels were markedly reduced from pretreatment levels but usually remained moderately elevated. There were 17 vascular events in 12 patients at a mean (range) age of 42.5 (18 to 67) years: pulmonary embolism (n=3), myocardial infarction (n=2), deep venous thrombosis (n=5), cerebrovascular accident (n=3), transient ischemic attack (n=1), sagittal sinus thrombosis (n=1), and abdominal aortic aneurysm (n=2). Without treatment, 112 vascular events would have been expected, for a relative risk of 0.09 (95% CI 0.036 to 0.228; P<0.0001). Treatment regimens designed to lower plasma homocysteine significantly reduce cardiovascular risk in cystathionine beta-synthase deficiency despite imperfect biochemical control. These findings may be relevant to the significance of mild hyperhomocysteinemia that is commonly found in patients with vascular disease.

Adolescent↗
PubMed2001

Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.

Compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and the R117H or R117C mutation (R117H/C) have clinical presentations that vary from classic cystic fibrosis (CF) to an incidental genetic finding. The aim of this study was to assess the influence of the intron-8 polythvmidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. All individuals with R117H/C known to CF clinics in Australia and New Zealand were retrospectively studied by collecting information on genotype, age, pancreatic status, sweat electrolytes, sputum microbiology and pulmonary function. Forty-one individuals (39 with R117H and two with R117C), 16 on an IVS8-5T background and 25 on an IVS8-7T background were identified. Twelve individuals presented clinically, four were siblings of known R117H/C compound heterozygotes and 25 were detected by newborn screening. Eleven of 14 of the IVS8-5T group (78%) with sweat chloride results available had sweat CI > 60 mmol x L(-1) compared to 5 (20%) of the R117H/7T group (Chi-squared=10.4, p=0.001). Two were pancreatic insufficient, both IVS8-5T. Two IVS8-5T individuals have recently died (aged 43 and 19) and of the 14 surviving IVS8-5T group, 11 (79%) are symptomatic compared to eight (32%) of the IVS8-7T individuals (Chi-squared=6.1, p=0.01). In conclusion, most individuals with R117H/C on a IVS8-5T background have an elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe. Most individuals with R117H/C on an IVS8-7T background do not have clinical cystic fibrosis but should be followed for the development of clinical disease.

Adolescent↗