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Biomedical subjects

W Rhead

Publications and source records attributed to W Rhead.

11 recordsLinked to original sources
PubMed2002

Phenylketonuria in adulthood: a collaborative study.

During 1967-1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty-five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status. Fourteen of the original clinics (1967-1983) participated in the Follow-up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967-1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations. The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.

Adult↗
PubMed1997

Stridor as the major presenting symptom in riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

UNLABELLED: Inspiratory stridor of unknown origin was the leading clinical symptom in an 11-month-old boy. The stridor increased over a period of 4 weeks, and assisted ventilation became necessary. Selective urinary screening by gas chromatography/mass spectrometry analysis revealed excretion of ethylmalonic and 3-OH-isovaleric acid and of N-isobutyryl-, N-2-methylbutyryl-, N-isovaleryl-, N-hexanoyl- and N-suberylglycine. Neither hypoglycaemia nor metabolic acidosis were noticed. Treatment with 200 mg of riboflavin per day led to a dramatic clinical improvement with restoration of normal respiration and an increase in muscular tone within 2 months. During this period, metabolite excretion in urine completely normalized. Riboflavin-sensitive multiple acyl-CoA dehydrogenation deficiency was confirmed in cultured fibroblasts. With riboflavin supplementation, the development of the child has been favourable, with normal school attendance now at an age of 9 years. CONCLUSION: As respiratory symptoms might precede other symptoms in disorders of mitochondrial oxidation, we propose determination of urinary organic acids in all cases of unexplained laryngeal stridor.

Adipates↗
PubMed1997

Deficient muscle carnitine transport in primary carnitine deficiency.

Primary carnitine deficiency is associated with deficient blood and tissue carnitine concentrations. The clinical syndrome is dominated by heart and skeletal muscle symptoms, and the clinical response to oral carnitine supplementation is life-saving. Carnitine uptake has been shown to be defective in cultured skin fibroblasts and leukocytes obtained from patients with this condition. We report a new case of primary carnitine deficiency and offer direct evidence consistent with an impairment of carnitine uptake in differentiating muscle culture. The patient presented with severe and progressive cardiomyopathy and moderate proximal limb weakness. Plasma and muscle carnitine levels were very low, and the maximal rate of carnitine transport in cultured fibroblasts was deficient. An asymptomatic sister with intermediate levels of carnitine in plasma showed partially deficient carnitine uptake in fibroblasts, indicating heterozygosity. The patient's condition improved dramatically with oral carnitine therapy. Further studies were performed in cultured muscle cells at different stages of maturation, which demonstrated deficient maximal rates of carnitine uptake. Our findings are consistent with the concept that primary carnitine deficiency is the result of a generalized defect involving carnitine transport across tissue membranes.

Biological Transport↗
PubMed1996

Prenatal ultrasound findings in hydrolethalus: continuing difficulties in diagnosis.

We present the prenatal ultrasound findings in a case of hydrolethalus. This case illustrates ongoing problems in differentiating hydrolethalus, both pre- and postnatally, from other midline malformation syndromes including Pallister-Hall, Smith-Lemli-Opitz, pseudo-trisomy 13, oral facial-digital syndrome, and Meckel syndrome. Hydrolethalus can also be difficult to distinguish from certain skeletal dysplasias such as the short rib-polydactyly syndromes and campomelic dysplasia. Tests which can aid in diagnosis are presented.

Adult↗
PubMed1993

Multiple acyl-coenzyme A dehydrogenation disorder responsive to riboflavin: substrate oxidation, flavin metabolism, and flavoenzyme activities in fibroblasts.

Multiple acyl-CoA dehydrogenation disorders result from generalized defects in intramitochondrial acyl-CoA dehydrogenation. Fibroblasts from a riboflavin-responsive multiple acyl-CoA dehydrogenation disorder patient catabolized 14C-butyrate, -octanoate, and -leucine normally after culture in riboflavin-supplemented medium (2 mg/L). After culture in riboflavin-depleted medium (< or = 1.4 micrograms/L), his cells oxidized the same substrates poorly at 20 to 33% of control (p < 0.05). Patient cells incubated in a wide range of D-[2-14C]riboflavin concentrations (3, 31.4, and 100 micrograms/L) synthesized 14C-flavin mononucleotide and 14C-flavin adenine dinucleotide (FAD) normally and had normal cytosolic 14C-flavin mononucleotide and 14C-FAD contents, which argues against defects in cellular riboflavin uptake and conversion to flavin mononucleotide and FAD. After culture in 31.4 micrograms 14C-riboflavin/L for 2 wk, 14C-FAD specific radioactivities plateaued and were similar in patient and control cells. However, culturing these uniformly labeled cells in riboflavin-depleted medium for 2 wk lowered the patient's cellular 14C-FAD content to only 23% of control levels. Similarly, after incubation in low 14C-riboflavin concentrations (4.4 micrograms/L), the patient's mitochondrial 14C-FAD content was only 51% of control after 1 h and 29% of control at 4 h. After a 4-h incubation in a high physiologic concentration of 14C-riboflavin (31.4 micrograms/L), which raised the patient's cellular 14C-FAD levels 3- to 4-fold, his mitochondrial 14C-FAD content rose to normal; control values did not change. We also investigated possible defective FAD binding to flavoenzymes essential for acyl-CoA dehydrogenation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl Coenzyme A↗
PubMed1991

The most common mutation causing medium-chain acyl-CoA dehydrogenase deficiency is strongly associated with a particular haplotype in the region of the gene.

RFLP haplotypes in the region containing the medium-chain acyl-CoA dehydrogenase (MCAD) gene on chromosome 1 have been determined in patients with MCAD deficiency. The RFLPs were detected after digestion of patient DNA with the enzymes BanII. PstI and TaqI and with an MCAD cDNA-clone as a probe. Of 32 disease-causing alleles studied, 31 possessed the previously published A----G point-mutation at position 985 of the cDNA. This mutation has been shown to result in inactivity of the MCAD enzyme. In at least 30 of the 31 alleles carrying this G985 mutation a specific RFLP haplotype was present. In contrast, the same haplotype was present in only 23% of normal alleles (P less than or equal to 3.4 x 10(-18)). These findings are consistent with the existence of a pronounced founder effect, possibly combined with biological and/or sampling selection.

Acyl-CoA Dehydrogenase↗
PubMed1989

Purified U5 small nuclear ribonucleoprotein can relieve the inhibition of spliceosome assembly and splicing by snRNP-free nuclear proteins.

As demonstrated by RNase T1 protection assays at 0 degrees C without ATP, U1 and U5 snRNPs purified by isopycnic centrifugation in cesium chloride bind to the 5' and 3' splice sites of human beta-globin pre-mRNA, respectively. We also devised a saturation-complementation assay and have found that this purified U5 snRNP, unlike U1, successfully competes with snRNP-free fractions of nuclear proteins which inhibit spliceosome assembly and splicing. Restoration of activity requires intact U5 snRNA and correlates with the presence of the 100 Kd intron binding protein (IBP) which we have previously characterized (Tazi et al., 1986, Cell 47, 755-766). Our results are compatible with a model in which the recognition of the 3' splice site by IBP-U5 snRNP is one of the earliest events of the spliceosome assembly. It could organize the structure of the 3' splice site region of the human beta-globin like pre-mRNAs. However, on the basis of results showing that beta-globin and major late adenovirus seem to have different requirements with respect to IBP-U5 snRNP, it appears that some pre-mRNAs could have a native structure that necessitates less if at all IBP-U5.

Centrifugation, Density Gradient↗
PubMed1987

Multiple congenital anomalies syndrome with myopathy in chromosome 16 abnormality.

An abnormality of chromosome 16 in an eight year-old male was associated with a multiple congenital anomalies syndrome characterized by myopathy, cataracts, blepharophimosis, microcephaly, failure to grow, profound mental retardation, moderate sensorineural hearing loss, grand mal seizures, bilateral inguinal hernia, and thoracolumbar kyphoscoliosis. Magnetic resonance imaging of the head demonstrated absence of the corpus callosum and extensive loss of brain parenchyma in the occipital regions. Chromosome analysis from peripheral blood of the patient showed a recombinant chromosome 16 [46, XY, rec (16), dup (p13.1----p13.3) del (q22----q24)]. The mother had a pericentric inversion of chromosome 16 [46, XX, inv(16) (p13.1;q22)]. Independent recombinant DNA studies have shown that the breakpoints of these chromosomal rearrangements flank the alpha-globin gene cluster locus.

Abnormalities, Multiple↗
PubMed1980

Glutaric aciduria type II: in vitro studies on substrate oxidation, acyl-CoA dehydrogenases, and electron-transferring flavoprotein in cultured skin fibroblasts.

The previous biochemical evidence had suggested that glutaric aciduria type II (GA II) is due to deficient dehydrogenation of multiple short-chain acyl coenzyme A's (CoA's), bu the precise biochemical mechanism underlying this disease was unknown. We investigated substrate oxidation and in vitro activities of isovaleryl CoA- and butyryl CoA dehydrogenases as well as that of electron-transferring flavoprotein (ETF) in cultured skin fibroblasts from a patient with GA II. GA II cells have a markedly decreased ability to oxidize [1-14C]butyrate, [2-14C]lysine, and [2,14C]leucine (3, 9, and 9% of control values, respectively). Mitochondrial isovaleryl CoA- and butyryl CoA dehydrogenase activities in GA II cells were determined using a tritium release assay with [2,3-3H] acyl-CoA's as substrate. When an artificial electron acceptor, phenazine methosulfate (PMS) was not added in the assay media, these activities were 108 and 113% of controls, respectively. This represents the normal abilities of the dehydrogenases in GA II cells to bind the substrate and to catalyze tritium exchange between the bound substrate and solvent. When PMS was added to the assay mixture, these activities were 88 and 70% of control values, respectively, indicating that these enzymes can both dehydrogenate their substrates normally and then transfer electrons to an acceptor (PMS). ETF activity in mitochondrial sonic supernatants from GA II cells, as assessed by a newly devised method, was 159% of control values. These observations suggest that the acyl CoA dehydrogenases themselves and ETF are not defective in GA II. Therefore, the deficiency of another common gene product necessary for the function of all the affected acyl CoA dehydrogenases must be sought to explain the etiology of GA II.

Acyl Coenzyme A↗