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Biomedical subjects

R J Pollitt

Publications and source records attributed to R J Pollitt.

At least 37 records · Page 2Linked to original sources
PubMed1997

Neonatal screening for cystic fibrosis in the Trent region (UK): two-stage immunoreactive trypsin screening compared with a three-stage protocol with DNA analysis as an intermediate step.

OBJECTIVES: To assess neonatal screening for cystic fibrosis using immunoreactive trypsin, either alone or in conjunction with DNA analysis for the delta F508 mutation. A novel three-stage screening protocol was compared with the previously introduced two-stage immunoreactive trypsin-DNA protocol. DESIGN: (a) Collection of data from a 4 1/2 year period (phase 1) of two-stage immunoreactive trypsin screening. The initial dried blood samples were obtained at 6 days of age and repeat samples at 27 days of age from babies with results above the 99.5th centile. Babies with persistent hypertrypsinaemia were referred for a diagnostic sweat test. (b) Retrospective DNA analysis: patients with cystic fibrosis diagnosed in phase 1 were genotyped and most samples from babies with increased initial immunoreactive trypsin but normal results in the second sample were analysed for the delta F508 mutation. (c) Phase 2, a prospective study of a three-stage neonatal screening protocol, in which only babies heterozygous for the delta F508 cystic fibrosis mutation progressed to the second immunoreactive trypsin test. SETTING: The Trent neonatal screening programme. SUBJECTS: 437 859 babies born between August 1989 and March 1996. MAIN OUTCOME MEASURES: Proportions of unaffected babies requiring a second blood sample or a sweat test. Overall sensitivity for the detection of cystic fibrosis. RESULTS: The two-stage screen failed to identify six out of 94 cases of cystic fibrosis (without meconium ileus). The introduction of the DNA analysis step would have resulted in one additional case being missed. With the three-stage screen there was a 92% reduction in babies requiring a second blood sample and an 80% reduction in negative sweat tests, results close to the predictions of the retrospective study. CONCLUSIONS: The three-stage screening protocol is a marked improvement on the two-stage immunoreactive trypsin strategy and on the two-stage immunoreactive trypsin-DNA strategy recently introduced in some other screening programmes.

Cystic Fibrosis↗
PubMed1997

Population screening for the common G985 mutation causing medium-chain acyl-CoA dehydrogenase deficiency with Eu-labeled oligonucleotides and the DELFIA system.

We have screened 10171 neonatal blood spots from the Trent and West Midlands regions of the UK for the common G985 mutation to more accurately establish the incidence of medium-chain acyl coenzyme (Co)A dehydrogenase (MCAD) deficiency. We have used a technique involving PCR and Eu-labeled allele-specific oligonucleotides detected by using time-resolved fluorometry on the dissociation-enhanced fluorescence immunoassay (DELFIA) system for the detection of the G985 mutation. We have also evaluated the feasibility of neonatal screening with this technique. We identified 158 G985 heterozygotes and no G985 homozygotes. The calculated incidence of MCAD deficiency in the population studied (all mutations, assuming 90% of MCAD mutations are G985) is 1 in 13426 (95% confidence limits 1 in 10070-1 in 18791). At the optimum cutoff criteria, the technique has a sensitivity of 97.5%, specificity of 99.6%, and positive predictive value of 80.2%. We conclude that this study confirms that MCAD deficiency is a common inherited metabolic disease and is a candidate for neonatal screening. The methodology used is robust and suitable for large-scale population studies such as this. The technique is also potentially suitable for screening.

Acyl-CoA Dehydrogenase↗
PubMed1997

Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

OBJECTIVES. To systematically review the literature on inborn errors of metabolism, neonatal screening technology and screening programmes in order to analyse the costs and benefits of introducing screening based on tandem mass-spectrometry (tandem MS) for a wide range of disorders of amino acid and organic acid metabolism in the UK. To evaluate screening for cystic fibrosis, Duchenne muscular dystrophy and other disorders which are tested on an individual basis. HOW THE RESEARCH WAS CONDUCTED. Systematic searches were carried out of the literature on inborn errors of metabolism, neonatal screening programmes, tandem MS-based neonatal screening technology, economic evaluations of neonatal screening programmes and psychological aspects of neonatal screening. Background material on the biology of inherited metabolic disease, the basic philosophy, and the history and current status of the UK screening programme was also collected. Relevant papers in the grey literature and recent publications were identified by hand-searching. Each paper was graded. For each disease an aggregate grade for the state of knowledge in six key areas was awarded. Additional data were prospectively collected on activity and costs in UK neonatal screening laboratories, and expert clinical opinion on current treatment modalities and outcomes. These data were used to construct a decision-analysis model of neonatal screening technologies, comparing tandem MS with the existing phenylketonuria screening methods. This model determined the cost per additional case identified and, for each disease, the additional treatment costs per case, and the cost per life-year saved. All costs and benefits were discounted at 6% per annum. One-way sensitivity analysis was performed showing the effect of varying the discount rate, the incidence rate of each disorder, the number of neonates screened and the cost of tandem MS, on the cost per life-year gained. RESEARCH FINDINGS. The UK screening programmes for phenylketonuria and congenital hypothyroidism have largely achieved the expected objectives and are cost-effective. Current concerns are the difficulty of maintaining adequate coverage, perceived organisational weaknesses, and a lack of overview. For many of the organic acid disorders it was necessary to rely on data obtained from clinically-diagnosed cases. Many of these diseases can be treated very effectively and a sensitive screening test was available for most of the diseases. Except for cystic fibrosis, there have been no randomised controlled trials of the overall effectiveness of neonatal screening. Despite the anxiety generated by the screening process, there is strong parental support for screening. The effects of diagnosis through screening on subsequent reproductive behaviour is less clear. Conflicts exist between current concepts and the traditional principles of screening. The availability of effective treatment is not an absolute prerequisite: early diagnosis is of value to the family concerned and, to the extent that is leads to increased use of prenatal diagnosis, may help to reduce the overall burden of disease. Neonatal screening is also of value in diseases which present early but with non-specific symptoms. Indeed, almost all of the diseases considered could merit neonatal screening. The majority of economic evaluations failed to incorporate the health benefits from screening, and therefore failed to address the value of the information which the screening programmes provided to parents. The marginal cost of changing from present technology to tandem MS would be approximately 0.60 pounds per baby at a workload of 100,000 samples a year, and 0.87 pounds at 50,000 samples per year. The ability to screen for a wider range of diseases would lead to the identification of some 20 additional cases per 100,000 infants screened, giving a laboratory cost per additional diagnosis of 3000 pounds at an annual workload of 100,000 babies per year.(ABSTRACT TRUNCATED)

Cost-Benefit Analysis↗
PubMed1996

Endocardial fibroelastosis and primary carnitine deficiency due to a defect in the plasma membrane carnitine transporter.

Endocardial fibroelastosis (EFE) has previously been shown to be associated with tissue carnitine deficiency, although the basis for the carnitine deficiency has not been documented. A patient with the classical features of EFE and marked deficiency of carnitine in heart muscle, skeletal muscle, and liver is presented in this report. Cultured skin fibroblasts from both parents demonstrated levels of carnitine uptake at 50% of the normal rate. This is consistent with heterozygosity for the plasma membrane carnitine transporter defect, indicating likely homozygosity for this recently recognized inborn error in the index patient.

Cardiomyopathy, Dilated↗
PubMed1995

Disorders of mitochondrial long-chain fatty acid oxidation.

The oxidation of long-chain fatty acids requires a series of enzymes which are located in or on the mitochondrial membranes. These include carnitine palmitoyltransferases I and II, a carnitine-acylcarnitine translocase and, newly discovered, very long-chain acyl-CoA dehydrogenase and the mitochondrial trifunctional protein. These last two chain-shorten acyl-CoA esters to the point where they can be transferred to the more soluble medium- and short-chain-specific enzymes within the mitochondrial matrix. The disorders of long-chain fatty acid oxidation show a rather similar range of clinical and biochemical features, though with different emphasis in the different conditions. Patients with severe defects usually present early with acute attacks of hypoketotic hypoglycaemia and impaired liver function, or with cardiomyopathy or cardiac arrhythmia. In milder variants, skeletal myopathy with intermittent myoglobinuria develops later in life. 3-Hydroxyacyl-CoA dehydrogenase deficiency is unusual in producing peripheral neuropathy and retinitis pigmentosa. Treatment is based on the avoidance of fasting and replacement of normal dietary fat by medium-chain triglyceride, the medium-chain fatty acids entering the mitochondria in a carnitine-independent manner and bypassing the long-chain part of the spiral. Diagnosis must ultimately be based on direct assay of the enzyme involved, but preliminary indicators may come from determination of carnitine and intermediate metabolites in plasma, urinary organic acid profiling, and radioisotopic screening assays with lymphocytes or cultured fibroblasts.

Fatty Acids↗
PubMed1995

Trichothiodystrophy with sideroblastic anaemia and developmental delay.

A patient with sideroblastic anaemia, development delay, and trichothiodystrophy is presented. Trichothiodystrophy is a feature of several autosomal recessive diseases. Photosensitivity, failure to thrive, and developmental delay are commonly observed in affected cases. X linked inheritance accounts for the bulk of cases with sideroblastic anaemia. This case highlights the importance of routine hair microscopy in cases of atypical ectodermal dysplasia.

Anemia, Sideroblastic↗
PubMed1994

Prenatal diagnosis of glutathione synthase deficiency.

Prenatal diagnosis for glutathione synthase (EC 6.3.2.3) deficiency in two pregnancies of an at-risk couple was performed on amniotic fluid taken at 16 weeks' gestation. 5-Oxoproline (pyroglutamic acid) levels were 970 and 790 mumol/l compared with the normal mean value of 29 mumol/l (range 13-51 mumol/l). The pregnancies were terminated and the diagnosis in one case was subsequently confirmed by assay of glutathione synthase in cultured fetal fibroblasts. In the other, post-mortem tissue samples failed to grow.

Adult↗
PubMed1994

6-Methyluracil excretion in 2-methylacetoacetyl-CoA thiolase deficiency and in two children with an unexplained recurrent ketoacidaemia.

6-Methyluracil (6MU) has been identified in urine collected during acute illness in two children with beta-ketothiolase deficiency (approximately 1 mmol/L) and in two children with recurrent infection-related ketoacidaemia of unknown aetiology (levels of 6.3 and 7.1 mmol/mmol creatinine). Significant amounts of 6MU were not detected in children with fasting ketosis in whom a metabolic disorder was excluded (normal levels less than 25 mumol/mmol creatinine). We propose that the production of 6MU may be related to the accumulation of acetoacetyl-CoA and thus be a marker for disorders where this occurs.

Acetyl-CoA C-Acetyltransferase↗
PubMed1994

Quality assessment of urinary organic acid analysis.

The number of known inherited metabolic disorders resulting in an organic aciduria has increased steadily over the past two decades. Prompt and reliable detection is both clinically and technically demanding but is essential if appropriate treatment is to be undertaken. This is the first study of laboratory performance in the detection of these disorders to be undertaken in the UK. Some conditions were accurately identified by most laboratories: for example for maple syrup urine disease, 12 of 14 laboratories provided an appropriate response and medium chain acyl-CoA dehydrogenase deficiency was correctly identified by 15 of 17 laboratories. However, accuracy of detection was poorer for other conditions: for example, only eight of 17 laboratories detected tyrosinaemia type 1 and nine of 18 laboratories detected 4-hydroxybutyric aciduria. The strongest correlation with good performance was obtained by comparison with the extent of peak identification: r = 0.62, P = 0.002. The need for regular attendance at scientific symposia was also supported by a weaker positive correlation with the average score achieved, P = 0.08. Evidence also suggested that some of the laboratories with a low workload performed less well. No significant difference in performance could be demonstrated between the 17 laboratories who used gas chromatography-mass spectrometry and the six participants who used gas chromatography alone.

Acyl-CoA Dehydrogenase↗
PubMed1994

Syndromes associated with trichothiodystrophy.

Sparse, brittle, sulphur-deficient hair is an excellent marker for several autosomal recessive neurocutaneous syndromes. The term 'trichothiodystrophy' is commonly used in publications on such syndromes and the best characterized trichothiodystrophy syndrome is associated with skin photosensitivity and intellectual impairment. Patients with these three cardinal signs usually have an underlying DNA repair defect. Here we describe clinical and laboratory findings in two patients with trichothiodystrophy and defective DNA repair alongside findings in three other cases who have different trichothiodystrophy syndromes without defective DNA repair. These patients' features are discussed in the light of a practical classification scheme which is based upon a check-list of clinical abnormalities associated with trichothiodystrophy syndromes (Van Neste, 1991).

Adolescent↗
PubMed1993

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency--diagnosis, plasma carnitine fractions and management in a further patient.

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), the third enzyme of the mitochondrial beta-oxidation pathway, carries out the dehydrogenation of 3-hydroxyacyl-CoA compounds of 12-18 carbon length. To date only nine cases of LCHAD deficiency have been documented. We report a further patient who as a neonate developed non-specific gastrointestinal symptoms and at 5 months of age cardiomyopathy, recurrent hypoketotic hypoglycaemia and gross alterations of plasma carnitine fractions. Dietary management with medium chain triglycerides led rapidly to clinical improvement. There was a close correlation between the clinical condition, plasma carnitine fractions and cardiac function. At 2 years of age she is developing normally.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1993

Neonatal screening.

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Congenital Hypothyroidism↗
PubMed1993

Familial hypercholesterolaemia: pilot study to identify children at risk.

AIMS: To evaluate a more effective method of identifying children with familial hypercholesterolaemia by screening a population at high risk. METHODS: Domiciliary measurement of random cholesterol concentration was made in 200 children who were first or second degree relatives of subjects with premature onset coronary artery disease. Measurements were taken by a health visitor using a portable analyser. RESULTS: Twelve new cases of familial hypercholesterolaemia were identified during the first nine months of the study. Random cholesterol concentrations were within the normal range (< 5.2 mmol/l) in 70.5% of samples tested. Forty two (21%) of patients tested had a borderline cholesterol (5.2-5.9 mmol/l) but 50% of these fell within the normal range when fasting capillary samples were analysed. Children with significant hypercholesterolaemia on random testing (concentrations of > 5.9 mmol/l) (8.5%) also had fasting venous blood assayed for high density lipoprotein (HDL) cholesterol and tri-glyceride in the laboratory. Results indicated that 6.5% of patients screened were at high risk of cardiovascular disease (ratio of total: HDL cholesterol of > 4.5), and 1% had a moderately increased risk (ratio 3.5-4.5). CONCLUSIONS: Children with familial hypercholesterolaemia can be identified from a selected "high risk" population by measuring random capillary cholesterol concentration.

Adolescent↗