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Biomedical subjects

C R Scriver

Publications and source records attributed to C R Scriver.

At least 181 records · Page 10Linked to original sources
PubMed1983

Histidinaemia. Part I: Reconciling retrospective and prospective findings.

We reach the conclusion that histidinaemia in the typical form (autosomal recessive impairment of L-histidine ammonia lyase activity (EC4.3.1.3)) is not a 'disease' in man. Retrospective and prospective studies (Rosenmann et al., 1983; Coulombe et al., 1983) together indicate that the prevalence of disadaptive phenotypes (e.g. impaired intellectual or speech development, seizures, behavioural or learning disorder) in the histidinaemia population, is not higher than the frequency of these functional disorders in the non-histidinaemia population. However, one cannot exclude the possibility that histidinaemia is a risk factor for development of an unfavourable CNS phenotype, in particular individuals under specific circumstances (e.g. abnormal perinatal events). From this viewpoint, we propose that newborn screening for early diagnosis and treatment of histidinaemia does not meet the criteria for a public health service. Screening for continuing research on histidinaemia remains justifiable, for example, to discern whether there are atypical forms of the biochemical and enzymatic phenotypes.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Histidinaemia. Part II: Impact; a retrospective study.

Forty-two articles published between 1961 and 1977 describing 43 probands and 26 siblings with histidinaemia were used for the retrospective study. Our objective was to describe the apparent impact of the mutation on development and health in human histidinaemia. The findings were similar to those of an earlier survey (Popkin et al., 1974). Most probands (79%) had a disadaptive CNS phenotype (mental retardation, impaired speech, seizures, aberrant behaviour, and/or learning disorder); half the histidinaemic siblings had a similar phenotype. The modal IQ score was 70; age at recognition of symptoms (CNS phenotype) varied from 1 month to 16 y (modal age 2 1/2 y). There was no correlation between blood histidine (reported values) and occurrence of severity of CNS phenotype. Thirty per cent of histidinaemia subjects, for whom the perinatal history was described, had an abnormal experience. Reported cases with the CNS phenotype apparently represent a very small fraction (about 1%) of all subjects with histidinaemia; this implies that the histidinaemia phenotype is not disadaptive in man.

Adolescent↗
PubMed1983

Histidinaemia. Part III: Impact; a prospective study.

We describe a prospective study of histidinaemia. Probands and siblings (n = 21) with typical histidinaemia in 16 families were ascertained by newborn screening; diagnosis was confirmed by appropriate investigations in each subject; none had been treated by low histidine diet. The median age of subjects with histidinaemia was 9.5 y (mean 10.0, SD 3.5, range 6-18). Age-matched sib-pairs and their mothers were studied. IQ scores (Full Scale, Verbal and Performance Scores), Visual-Motor Integration Performance (Bender Gestalt and Koppitz scores), Wide Range Achievement Test (Reading and Mathematics), school performance, and psychological history were evaluated, as well as the medical history (pregnancy, delivery, neonatal, post-natal development). Findings were correlated with biochemical phenotype. CNS development in histidinaemic subjects (mean and distribution of scores) was normal; outlier values did not correlate with degree of histidinaemia. We can conclude that histidinaemia detected by newborn screening is a non-disadaptive phenotype.

Adolescent↗
PubMed1983

Hypertaurinuria in the C57BL/6J mouse: altered transport at the renal basolateral membrane.

The C57BL/6J mouse is an inbred strain with selective hypertaurinuria. C3H/HeJ mice (control) and C57BL/6J mice have comparable values for plasma taurine and renal creatinine clearance but significantly different fractional taurine excretion: C3H mice, 0.15 +/- 0.03; C57BL mice, 0.44 +/- 0.08 (P less than 0.01). C57BL mice fed control diet have significantly higher renal cortex taurine (11.5 +/- 0.4 mumol/g wet wt, mean +/- SE) relative to C3H mice (10.5 +/- 0.5 mumol/g, P less than 0.05); the difference is magnified when mice are fed low protein or low sulfur amino acid diet and experience renal adaptation with enhanced taurine transport at the luminal membrane (P less than 0.01). Taurine transport by purified brush border membrane vesicles is similar in the two strains fed control diet. On the other hand, renal cortex slices show the following differences: 1) net uptake of taurine at 0.11 mM is lower in C57BL slices at initial rates and at steady state; 2) the difference in uptake between strains is magnified in the presence of phlorizin, an inhibitor of taurine efflux; 3) efflux of taurine from preloaded slices is less per unit time in C57BL mice; and 4) uptake differences are specific for taurine. These findings are not accountable to differences in taurine oxidation, slice weight, or water spaces. They indicate that hypertaurinuria in the C57BL/6J strain is a function of decreased basolateral membrane permeability to taurine at physiologic concentrations.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Metabolism of methylmalonic acid in rats. Is methylmalonyl-coenzyme a racemase deficiency symptomatic in man?

Vitamin B12-deficient and normal rats were loaded with methylmalonic (MMA) and ethylmalonic acids labeled with 13C in the carboxyl groups and with 2H in the alkyl groups. Significant fractions of the administered acids were excreted in both the B12-deficient and the normal animal, having undergone exchange of both their 13C-labeled carboxyl groups with endogenous 12C. The exchange of the alpha-1H of MMA in 2H2O at 25 degrees C and pH 7.5 was found by 1H-nuclear magnetic resonance to have a half-life of 28.3 min. These results show that a fraction of in vivo metabolism through the propionate-to-succinate pathway occurs via a shunt involving free MMA. The enzymes of this pathway are thought to utilize only coenzyme A (CoA) esters. To allow for the exchange of the second CoA-bound carboxyl group, we propose the deacylation of the once exchanged acid with spontaneous racemization (relative to the 13C-carboxyl group), followed by reacylation, thus exposing the labeled carboxyl to decarboxylation. The significance of this mechanism involving free MMA is that racemization of methylmalonyl (MM)-CoA may also occur without the intervention of MM-CoA racemase. A deficiency of this enzyme need not result in symptomatic methylmalonic aciduria.

Animals↗
PubMed1983

Secreted collagen ratios in normal human and osteogenesis imperfecta skin fibroblasts.

We examined the effects of several variables on the ratio of type I:type III collagen secreted by human caucasian skin fibroblasts in normal and osteogenesis imperfecta (OI) phenotypes. Isotopically labelled collagen extracted from fibroblast medium was analyzed by DEAE-cellulose chromatography and identified by appropriate methods. Type I procollagen was the major form of collagen secreted into the medium by normal cells cultured from one mid-term fetus, infants (n = 3), children (n = 3), adolescents (n = 2), and adults (n = 3). Interstrain differences in collagen production under standardized conditions were significantly greater than intrastrain variation (anova, p = 0.0051). There was no significant alteration in the type I:type III collagen ratio due to variation in: phase of cell growth, doublings (between 13th and 22nd), rate of isotope incorporation, labelling time (24-72 hrs) in the presence of ascorbic acid (50 micrograms/ml), age of donor (with the possible exception of adolescence), and site of biopsy (genital and non-genital sites). Variable conversion of type I procollagen to collagen did not perturb the type I:type III collagen ratio. Cell strains from OI patients (Sillence classification): type I (one strain); type II, III and IV (3 strains each) had greater interstrain than intrastrain variation in the collagen ratio (p = 0.0149). Interstrain differences were greater in OI cell strains relative to normal cell strains (p less than 0.01). In the aggregate, OI cells had significantly lower type I collagen production relative to type III (I/III ratio = 1.18) when compared with normal cells (I/III ratio = 2.90; t test, p less than 0.0001). These findings imply abnormal synthesis, secretion or stability of type I procollagen and greater phenotypic heterogeneity in OI skin fibroblasts relative to normal cells.

Adolescent↗
PubMed1983

A perimortem protocol for suspected genetic disease.

A considerable portion of pediatric deaths represent disease with risk of recurrence in subsequent family members. Procedures to obtain samples of body fluids and tissues suitable for diagnosis of mendelian and chromosomal disorders are described. These procedures, the "perimortem protocol," are used in studying children who died of suspected but undiagnosed genetic disease.

Chromosome Aberrations↗
PubMed1982

Topology of membrane exposure in the renal cortex slice. Studies of glutathione and maltose cleavage.

We measured glycine release from ([2-3H]glycine)-labelled GSH and glucose formation from maltose incubated with rat kidney whole cortex homogenate, thin cortex slices or collagenase-treated tubule fragments. Liberation of glycine was inhibited (74-83%) by serine borate (20 mM), indicating a gamma-glutamyltransferase-dependent hydrolysis of GSH. In whole cortex homogenate, the GSH cleavage activity was 17.4 +/- 0.6 nmol GSH degraded/mg protein per min (mean +/- S.D.); cleavage activity by intact slices was 3.5 +/- 0.7 (P less than 0.001 relative to whole cortex homogenate) and in tubule fragments 9.4 +/- 0.8 (P less than 0.001). Homogenizing the tissue preparation increased cleavage rate in slices about 4-fold (12.4 +/- 2.9; P less than 0.005 relative to intact slice) but did not change the rate in tubule fragments (9.8 +/- 0.5). Maltose cleavage activity in whole cortex homogenate was 512 +/- 22 nmol glucose formed/mg protein per min, in slices 162 +/- 12, and in tubules 884 +/- 48. These findings imply that substrate in the incubation medium has a limited access to the luminal membrane of cortex slices but not of tubule fragments. They further imply that basolateral membrane is preferentially exposed in the slice preparation.

Animals↗
PubMed1982

Properties of gamma-aminobutyric acid synthesis by rat renal cortex.

Substantial synthesis of gamma-aminobutyric acid occurs in rat renal cortex. Renal glutamate decarboxylase activity (24.3 +/- 2.9 (S.E.) nmols/mg protein per h) is 15% of that in brain; renal gamma-aminobutyric acid content (39.5 +/- 5.3 (S.E.) nmols/g wet wt.) is 5% of the whole brain concentration. Properties of glutamate decarboxylase were studied in homogenates of rat renal cortex and rat brain under conditions for which gamma-aminobutyric acid formation from [2,3-3H]glutamate and CO2 release from [1(-14)C]glutamate were equal. Several properties of renal glutamate decarboxylase distinguish it from the corresponding brain enzyme: (1) renal glutamate decarboxylase is selectively inhibited by cysteine sulfinic acid (Ki = 5X10(-5) M); (2) renal glutamate decarboxylase is less sensitive (Ki = 3-5X10(-5) M) to inhibition by aminooxyacetic acid than is the brain enzyme (Ki = 1X10(-6) M); (3) brain but not renal glutamate decarboxylase activity can be substantially stimulated in vitro by the addition of exogenous pyridoxal 5'-phosphate; (4) renal glutamate decarboxylase is significantly decreased in renal cortex from rats on a low-salt diet. Proximal tubules are enriched in glutamate decarboxylase compared to the activity in whole renal cortex or glomeruli (42, 22 and 14 nmols/mg protein per h, respectively). We speculate that renal gamma-aminobutyric acid synthesis does not reflect the presence of GABAergic renal nerves, but may serve a function in proximal tubular cells.

Animals↗
PubMed1982

Inorganic sulfate in cerebrospinal fluid from infants and children.

Inorganic sulfate in cerebrospinal fluid (CSF) from 25 infants and children was measured by controlled-flow anion chromatography. The mean CSF concentration was 0.133 +/- 0.066 mumol/l for the group. Mean CSF sulfate is age dependent being 0.170 mmol/l in the newborn and 0.095 mmol/l (range: 0.059-0.165) in children over 3 years of age. The fall in CSF sulfate parallels a corresponding age-dependent change in serum sulfate. Accordingly, the CSF:serum ratio (0.334 +/- 0.019; mean +/- SE) remains constant in infants and children. The CSF:serum ratio departs significantly from that predicted by the Gibbs-Donnan equilibrium relation (predicted ratio, 1.21). CSF sulfate content appears to reflect mediated transport of sulfate out of CSF.

Adolescent↗
PubMed1982

Renal transport of taurine adapts to perturbed taurine homeostasis.

Renal adaptation apparently contributes to the homeostasis of taurine, a beta-amino compound that behaves as a conserved metabolite in the mammal. We studied two strains of inbred mice: C3H/HeJ (low-taurine excreter) and C57BL/6J (high-taurine excreter due to impaired basolateral membrane permeability to taurine). Low-protein and low-sulfur amino acid diets fed for two weeks significantly decreased plasma taurine in both strains, decreased fractional taurine excretion in vivo (particularly in the C57BL strain), and increased net uptake of taurine by renal cortex slices and isolated brush-border membrane vesicles (BBMV) in vitro in both strains. Renal adaptation was less obvious in vivo in the low-taurine excreter C3H strain, but in vitro adaptation, as observed in slices and BBMV (P less than 0.01), was greater than that observed in the C57BL strain. Renal cellular taurine content fell (P less than 0.01) only in the adapted C3H strain. The in vitro adaptive response was not confined to taurine; BBMV uptake of D-glucose and L-alanine was also enhanced in the adapted state. Specificity of the stimulus for adaptation was tested with a low-phenylalanine diet; a modest adaptation was observed in vivo and in vitro but only in the C3H strain. BBMV adaptation did not correlate with blood methionine but correlated inversely with plasma taurine (r = 0.71, P less than 0.05), implying that change in extracellular taurine may be a signal for renal adaptation in taurine homeostasis in the mammal.

Amino Acids↗
PubMed1982

Cystinotic and normal fibroblasts: differential protection in cystine-free medium by dithiothreitol.

We studied survival of normal (n=4) and cystinotic (n=3) fibroblast strains in selective (cystine-free) medium, with or without dithiothreitol (DTT)-thiol or disulfide. Cells were plated at low density first in maintenance medium (containing cystine), then washed and exposed to selective medium for 24 hr or longer. Cultures were trypsinized at specified times and the cells counted. Selective medium caused progressive detachment (greater than 90% by 72 hr) of control and cystinotic cells: DTT-disulfide (4 mM) and DTT-thiol (0.5 mM) both protected cystinotic cells (p less than 0.02) but not control cells in selective medium. DTT-thiol (0.5 mM) and DTT-disulfide (4mM) both depleted the intracellular non-protein cystine pool of cystinotic cells to less than 25 percent of pretreatment levels. Cystinotic cells preincubated with cysteamine (1 mM X 4 hr) to deplete the intracellular cystine pool were not protected by DTT-disulfide than with DTT-thiol. These findings imply that mobilization of intracellular cystine protects cystinotic cells in selective medium; cystinotic fibroblasts can utilize DTT-disulfide as well as DTT-thiol to mobilize cystine.

Culture Media↗
PubMed1982

Neonatal iminoglycinuria: evidence that the prolinuria originates in selective deficiency of transport activity in the proximal nephron.

We investigated the process of neonatal hyperprolinuria in dog and rat. Plasma proline varied only 2-fold in the puppy whereas prolinuria increased up to 12-food from birth to the 10th day declining thereafter to reach adult values (less than 0.1 mumole/mg creatine) by the third wk. Stop-flow analysis in puppies (less than 17 days old, n = 3) and one adult dog revealed that backflux of proline in distal nephron is not the source of neonatal hyperprolinuria. Prolinuria occurs in the Long-Evans rat pup during the first postnatal wk. We measured net uptake of L-proline at low (0.2 mM) and high (5 mM) concentrations by tubule fragments prepared form newborn and adult kidneys. At both concentrations and at initial rates, uptake was similar in newborn and mature tubules; at or near steady-state, tubules of newborn kidney had greater net uptake relative to mature kidney, apparently because efflux is attenuated. A difference in metabolic runout did not explain the difference in proline uptake by newborn kidney. Tubules from pups less than 7 days old did not exclude the competitive inhibitor AIB from interacting with proline uptake at o.2 mM when compared with mature kidney, (p = 0.005). These findings imply that transport of proline on the previously described proline-preferring high-affinity system is deficient in proximal nephron of newborn kidney.

Animals↗
PubMed1982

Prevention of mental retardation in offspring of hyperphenylalaninemic mothers.

Maternal hyperphenylalaninemia constitutes a potential hazard to the fetus for whom the risks of postnatal mental retardation, microcephaly, and congenital malformations are elevated. Preconception and intragestational dietary treatment can apparently improve the outcome of such pregnancies. In the absence of predictive mechanisms for pregnancies at risk and preventive measures involving reproductive counseling and treatment, there could be a rebound in the population frequency of mental retardation related to disorders of phenylalanine metabolism in subsequent generations. We describe a program serving a population of six million that includes screening, diagnosis, treatment, and counseling of the hyperphenylalaninemias. The program has recently added a simple dedicated register for males and females with hyperphenylalaninemia to supplement traditional methods for continuous surveillance of probands. We registered 153 patients: 43 females and 56 males with phenylketonuria, 23 females and 31 males with benign hyperphenylalaninemia, of which 22, 7, 27 and 5, respectively, had reached their 12th birthday in an 1981. Regional centers in the program provided counseling about the consequences of maternal hyperphenylalaninemia and the options to prevent them. No family has rejected the principle or fact of the Register and its goals.

Adolescent↗
PubMed1981

Microassay of inorganic sulfate in biological fluids by controlled flow anion chromatography.

The application of controlled flow anion chromatography to the assay of inorganic sulfate in biological fluids is described. The sulfate anion is separated from other anions by ion-exchange chromatography and quantitated conductimetrically. Coefficient of variance is 3.4%, about half that for the barium precipitation assay. Interference from heparin in plasma samples and unknown sources in tissue extract analysis is avoided. Sulfate levels in plasma are not different from those measured in serum after protein precipitation. Normal levels for sulfate concentration in human plasma, cerebrospinal fluid and hepatic tissue extract are reported.

Adult↗