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D J Carson

Publications and source records attributed to D J Carson.

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

Mutational studies of yeast transcription factor IIB in vivo reveal a functional surface important for gene activation.

Recent experiments in yeast (Saccharomyces cerevisiae) cells have identified a species-specific region of yeast transcription factor IIB (TFIIB) located at residues 144-157. According to the human TFIIB structure, this region is part of a solvent-exposed helix in the first repeat of the carboxyl-terminal core domain. In this report, we systematically analyze four positions in this region (Lys-147, Cys-149, Lys-151, and Glu-152) that together have been shown previously to be important for yeast TFIIB's function in vivo. Our experiments suggest that all of these four positions, and in particular positions 151, 149, and 152, are critical for yeast TFIIB's ability to support cell growth. In addition, we describe an intragenic suppressor screening experiment to identify mutations that reverse, or partially reverse, the temperature-sensitive phenotype of a yeast TFIIB derivative bearing amino acid changes at these four positions to human residues. The suppressor mutations reveal changes at positions 115, 117, and 182 that are located outside the species-specific region of yeast TFIIB, suggesting an extended surface available to interact with other proteins. Finally, we demonstrate that the suppressor mutations restore gene activation in vivo, further supporting the idea that one important function of yeast TFIIB in living cells is to mediate gene activation.

Amino Acid Sequence↗
PubMed1997

Fractures and phenylketonuria.

Parent or self-reported history of fractures in a group of patients aged from 0.3 to 33.6 years on dietary treatment for phenylketonuria was studied by means of a questionnaire. Twenty-one of 85 patients had a history of fracture compared with 18/98 sibling controls. There was no significant difference in the lifetime risk of fracture between patients and controls (chi 2 = 1.43, df = 1, p = 0.23), but a significantly higher risk of fracture was reported over the age of 8 y (chi 2 = 5.11, df = 1, p = 0.024), with a relative risk of 2.6 (95% confidence interval 1.1.6.1). We suggest this may be related either to deterioration in dietary control in this age group or to a cumulative disease-related or diet-related reduction in bone mass.

Adolescent↗
PubMed1996

Epidemiology of childhood IDDM in Northern Ireland 1989-1994: low incidence in areas with highest population density and most household crowding. Northern Ireland Diabetes Study Group.

During the period 1989-1994, 462 cases of insulin-dependent diabetes mellitus were registered among children from Northern Ireland aged under 15 years. The estimated completeness of the register was 98.8% (95% confidence interval (CI) 97.7%, 99.9%). A standardised rate of 19.6 (95% CI 17.8, 21.4) per 100 000 person years was obtained, placing Northern Ireland near the top of the range of published incidence in the United Kingdom, with a rate close to that reported for Scotland. In an analysis based on 217 postcode sectors, areas with a high population density and the most material deprivation were observed to have the lowest incidence rates. After inclusion of population density in a Poisson regression analysis, the component of deprivation which was found to be most significant was household crowding. Relative to children living in areas of low population density, there was a reduced risk for children in medium (relative incidence 0.85 (95% confidence limits CI 0.67, 1.09)) and high (0.62 (95% CI 0.48,0.80)) population density areas. Similarly, relative to children living in areas with low levels of household crowding, there was a reduced risk for children in medium (relative incidence 0.73 (95% CI 0.58,0.93)) and high (0.67 (95% CI 0.53, 0.83)) levels of household crowding. Tests for space-time clustering at diagnosis and at birth were negative. A possible explanation for the differences in incidence rate observed in this study is that exposure to infections very early in childhood is a protective factor. Later infections may act as either initiators or promoters of diabetes, but the absence of space-time clustering suggests that no single specific infectious agent is responsible.

Adolescent↗
PubMed1996

Wolcott-Rallison syndrome associated with congenital malformations and a mosaic deletion 15q 11-12.

Wolcott-Rallison syndrome is a rare autosomal recessive condition first described in 1972. It is characterised by diabetes mellitus which arises in early infancy and multiple epiphyseal dysplasia. We describe an affected girl who had recurrent episodes of hepatic failure for which no obvious cause was found. Post-mortem examination revealed abnormal pancreatic histology and congenital abnormalities of the central nervous and cardio-respiratory systems which have not been previously described in this condition. She also demonstrated a deletion at 15q 11-12 in 65% of her cells.

Abnormalities, Multiple↗
PubMed1996

Necropsy findings in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism, characterised by defective transport of the cationic amino acids lysine, arginine and ornithine. To date there are few reported necropsy cases. This report describes the necropsy findings in a 21 year old female patient originally diagnosed as having LPI in 1973. Liver function tests deteriorated and immediately before death jaundice, hyperammonaemia, coma, metabolic acidosis, and a severe bleeding diathesis developed. At necropsy, there was micronodular cirrhosis of the liver with extensive fatty change in hepatocytes. The lungs showed pulmonary alveolar proteinosis. Immunofluorescence and electron microscopy revealed the presence of a glomerulonephritis with predominant IgA deposition. These necropsy findings reflect the spectrum of lesions reported in LPI, providing further evidence of an association between this condition and pulmonary alveolar proteinosis, cirrhosis and glomerulonephritis.

Adult↗
PubMed1995

Radiological assessment of the hand and wrist in phenylketonuria and hyperphenylalaninaemia.

A radiograph of the left hand and wrist was taken in 141 children and young adults with phenylketonuria and hyperphenylalaninaemia. Ten (7.1%) had a bony abnormality and, of these, six (4.3%) showed evidence of reduced bone density. Only one patient had evidence of spiculation of the lower ulnar metaphysis previously described in phenylketonuria. Bone maturity was also assessed in 130 patients by the Tanner-Whitehouse (TW2) method. In 28 patients (21.5%) bone age was less than chronological age by 1 year or more. Bone age delay was greater in younger children on a more restricted diet with a lower intake of natural protein.

Adolescent↗
PubMed1995

Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach.

We present a multistep approach for the rapid analysis of phenylketonuria (PKU) mutations. In the first step, three common mutations and a polymorphic short tandem repeat (STR) system are rapidly analyzed with a fluorescent multiplex assay. In the second step, minihaplotypes combining STR and VNTR data are used to determine rare mutations likely to be present in an investigated patient, which are then confirmed by restriction enzyme analysis. The remaining mutations are analyzed with denaturant gradient-gel electrophoresis and sequencing. The first two steps together identify both mutations in 90%-95% of PKU patients, and results can be obtained within 2 d. We have investigated 121 Northern Irish families with hyperphenylalaninemia, including virtually all patients born since 1972, and have found 34 different mutations on 241 of the 242 mutant alleles. Three mutations (R408W, I65T, and F39L) account for 57.5% of mutations, while 14 mutations occur with a frequency of 1%-6%. The present analysis system is efficient and inexpensive and is particularly well suited to routine mutation analysis in a diagnostic setting.

Base Sequence↗
PubMed1994

Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: frequent mutation allows screening and early diagnosis.

Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninaemia, i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different phenylalanine hydroxylase mutations in a particular population, non-PKU HPA is usually caused by the combined effect of a mild HPA mutation and a severe PKU mutation. Presented here is a comprehensive analysis of non-PKU HPA in Northern Ireland. Of particular interest is one prevalent HPA mutation (T380M), which is present in over 70% of non-PKU HPA patients in Northern Ireland. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU hyperphenylalaninaemia in the majority of cases at a very early stage. This may be clinically useful and reassuring for the parents. Other mutations described are V245A, L194P, and E390G.

Adolescent↗
PubMed1994

Automated sequencing detects all mutations in Northern Irish patients with phenylketonuria and mild hyperphenylalaninaemia.

In the first phase of the Northern Ireland PKU Study, we used automated sequencing to identify the spectrum of mutations in a random group of 32 unrelated phenylketonuria (PKU) families. We also investigated 7 Northern Irish patients with mild hyperphenylalaninaemia not requiring dietary intervention (MHP, previously referred to as non-PKU HPA). Disease-causing mutations were identified on all 78 investigated chromosomes. We found 23 different mutations, including 20 missense, 1 nonsense and 2 splice site mutations. All mutations were located within exons or at intron-exon boundaries of the phenylalanine hydroxylase gene. Seven mutations occurred at CpG sites, confirming these sites as mutation hot-spots in PKU. Mutations R408W and I65T are the two commonest PKU mutations in the Northern Irish population. Two mutations (T380M and V245A) can be characterized as MHP mutations; they are quasi dominant markers for MHP since they cause mild hyperphenylalaninaemia even when occurring in conjunction with the most severe PKU mutations. The results have proven valuable for the development of a routine PKU mutation analysis system in Northern Ireland.

DNA Mutational Analysis↗
PubMed1994

A case-control investigation of perinatal risk factors for childhood IDDM in Northern Ireland and Scotland.

OBJECTIVE: To identify perinatal risk factors for childhood insulin-dependent diabetes mellitus (IDDM) and determine if they differ between early-onset and late-onset disease. RESEARCH DESIGN AND METHODS: We selected 258 diabetic children in Northern Ireland and 271 diabetic children in Scotland from population-based registers. For each diabetic child, five matched control subjects were drawn from the same population. All perinatal data were recorded routinely at birth. Odds ratios (ORs) were estimated for parental age, social class, breast-feeding, deprivation measures, and other perinatal variables. RESULTS: Scottish data indicated an increased risk among children born to older mothers (OR = 2.43, 95% confidence interval [CI] 1.49-3.97 for mothers > or = 35 years of age relative to those < 25 years of age). Northern Ireland data showed no such effect. Only Northern Ireland data showed an excess risk in children of professional or managerial families (OR = 1.51, 95% CI 1.11-2.04). A small but nonsignificant reduction in risk among breast-fed children was observed only after adjustment for social class (OR = 0.76, 95% CI 0.54-1.07). Deprivation measures were associated with reductions in risk. Children delivered by cesarean section were at increased risk in both Northern Ireland (OR = 1.66, 95% CI 1.10-2.50) and Scottish (OR = 1.70, 95% CI 1.12-2.59) data. In Northern Ireland data only, children of first pregnancies were at increased risk (OR = 1.41, 95% CI 1.03-1.93). Both data sets indicated that a first pregnancy was a more important risk factor for early-onset disease than for late-onset disease. CONCLUSIONS: Many reported risk factors are weak and show inconsistencies between studies. They may be secondary to more direct, as-yet-undiscovered risk factors. Although irrelevant in the majority of cases, the increased risk associated with delivery by cesarean section deserves further study.

Adult↗
PubMed1992

Power spectral analysis of the electrocardiogram in diabetic children.

In recent years it has been shown that alteration in heart rate variability can be used for the objective assessment of autonomic function in adult diabetic patients. Using a microcomputer based system for on-line monitoring and analysis of heart rate variability by power spectral analysis, 100 children with Type 1 (insulin-dependent) diabetes mellitus were studied. A highly significant negative correlation was identified between heart rate variability and duration of diabetes (r = -0.88, p less than 0.0001). The mean heart rate variability in patients with diabetes of duration 3 years or more was significantly lower in comparison to age-matched control subjects. A highly significant negative correlation was evident between heart rate variability and mean HbA1 in patients with duration of diabetes of 5 years or more. A mean HbA1 over 10% during this period was associated with the greatest reduction in heart rate variability. Serial measurements of heart rate variability in diabetic children may be of predictive value prior to the onset of symptomatic neuropathy.

Adolescent↗
PubMed1991

Facio-cardio-renal (Eastman-Bixler) syndrome.

We report on a 5-year-old boy with moderate mental retardation, horseshoe kidneys, tricuspid valve prolapse, and a characteristic face with broad nasal root, prominent ears, and a cleft palate. These manifestations suggested the diagnosis of the Eastman-Bixler syndrome. Our patient also had an isolated growth hormone deficiency which responded successfully to treatment.

Abnormalities, Multiple↗
PubMed1990

Neuroblastoma in a patient with dihydropteridine reductase deficiency.

Tetrahydrobiopterin (BH4) deficiency is a rare cause of hyperphenylalaninaemia (HPA) and usually leads to progressive neurological deterioration despite early dietary control of plasma phenylalanine concentrations. Dihydropteridine reductase (DHPR) deficiency is the most severe cause with respect to a fatal outcome. We report a 7-year-old girl with HPA diagnosed on neonatal Guthrie screening who at the age of 6 months had cytotoxic therapy for an adrenal neuroblastoma which secreted catecholamines. When 4 years old she was found to have DHPR deficiency. Although developmentally retarded and microcephalic she has failed to develop the florid neurological features often associated with the condition.

Adrenal Gland Neoplasms↗
PubMed1990

Osteopenia and phenylketonuria.

Trabecular bone mineral content was assessed by quantitative computed tomography in eleven young adults with phenylketonuria who had been treated from early childhood with a diet restricted in natural protein and supplemented with amino acids, minerals and vitamins. There was a significant reduction in the bone mineral content of patients compared with the normal population. Prospective studies are indicated in younger patients to ensure optimum bone mineralisation is achieved by adulthood.

Adult↗
PubMed1990

Potentially life-threatening cardiac dysrhythmia in a child with selenium deficiency and phenylketonuria.

Selenium deficiency is a frequent finding in children with phenylketonuria (PKU) receiving dietary treatment. We report the occurrence of episodic ventricular tachycardia in a 9-month-old infant with PKU. Serum selenium (Se), 0.13 mumol/l (normal range 0.28-1.12 mumol/l, mean +/- 2 SD), and whole blood glutathione peroxidase (GSHPX), 16 U/g Hb (normal range 19.5-34.3 U/g Hb, mean +/- 2 SD), were low. Auscultation of cardiac rhythm is recommended during the routine follow-up of young children with PKU. Se deficiency should be considered in the aetiology of a dysrhythmia and corrected with Se supplementation.

Diet Therapy↗