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B Fowler

Publications and source records attributed to B Fowler.

At least 73 records · Page 4Linked to original sources
PubMed1997

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Adolescent↗
PubMed1997

Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans.

Elevated plasma homocysteine concentration is an independent risk factor for vascular disease in humans. In addition to nutritional and genetic factors, an interruption of the coordinate regulatory function of S-adenosylmethionine has been proposed to be involved in the occurrence of hyperhomocysteinemia. The effect of oral S-adenosylmethionine on homocysteine metabolism in humans is unknown. We investigated the effect of oral S-adenosylmethionine (400 mg) on plasma levels of 5-methyltetrahydrofolate, which is the active form of folate in the remethylation of homocysteine to methionine, S-adenosylhomocysteine, the demethylated product of S-adenosylmethionine, homocysteine and methionine over 24 hr in 14 healthy subjects. After oral administration, S-adenosylmethionine increased from 38.0 +/- 13.4 to 361.8 +/- 66.4 nmol/liter (mean +/- S.E., P < .001) and returned to base-line values with a half-life of 1.7 +/- 0.3 hr. Both S-adenosylhomocysteine and 5-methyltetrahydrofolate showed a significant transient increase (from 29.9 +/- 3.7 to 51.7 +/- 7.1 nmol/liter, and from 25.1 +/- 2.5 to 36.2 +/- 3.5 nmol/liter, respectively, P < .001), although homocysteine and methionine did not change over the time of measurement. These changes were not found in subjects without previous S-adenosylmethionine administration. The observed metabolic changes suggest that S-adenosylmethionine, at least in concentrations obtained in this study, does not inhibit 5,10-methylenetetrahydrofolate reductase, the 5-methyltetrahydrofolate forming enzyme. Rather they indicate a positive effect on 5-methyltetrahydrofolate, a key cofactor in homocysteine metabolism, which should be considered in homocysteine lowering strategies for the prevention of vascular disease.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1997

Slowing due to acute hypoxia originates early in the visual system.

BACKGROUND: Experiments in the visual modality show that acute hypoxia slows the earliest stage of information processing-preprocessing. It is unknown, however, whether a later stage, feature extraction, is also slowed. METHODS: To answer this question, an additive factors method (AFM) experiment was conducted which employed seven well trained subjects whose arterial oxyhaemoglobin saturation was controlled at 63% with low oxygen mixtures. The subjects responded to oddball names presented on a computer screen and both reaction time (RT) and the event-related brain potential P300 were measured. The luminance and quality of the names was varied factorially to influence the preprocessing and feature extraction stages, respectively. RESULTS: RT and P300 latency showed the same pattern of results: stimulus luminance and signal quality were additive, indicating that AFM assumptions were met; hypoxia and stimulus luminance were interactive but hypoxia and signal quality were additive. CONCLUSION: In conjunction with other evidence, we interpret these results to indicate that the locus of slowing produced by hypoxia is largely at the preprocessing stage, at least in the visual modality. Slowing at the preprocessing stage can be explained by hypoxia shifting the function relating RT and stimulus luminance to the right by a constant amount.

Acute Disease↗
PubMed1996

Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis.

BACKGROUND: Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. METHODS: We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. RESULT: Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of four patients with homocystinuria who did not have factor V Leiden, none had thrombosis (ages at this writing, 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. CONCLUSIONS: Patients with concurrent homocystinuria and factor V Leiden can have an increased risk of thrombosis. Screening for factor V Leiden may be indicated in patient with homocystinuria and their family members.

Adolescent↗
PubMed1996

Effect of methionine loading on 5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocysteine in plasma of healthy humans.

1. Elevated plasma homocysteine concentration, either in the fasting state or after methionine loading, is an independent risk factor for vascular disease in man. Methionine loading has been used to investigate impaired methionine metabolism, especially of the trans-sulphuration pathway, but most studies have focused on changes in homocysteine. 2. We investigated the effect of methionine excess on total plasma homocysteine, 5-methyltetrahydrofolate (which is the active form of folate in the remethylation of homocysteine to methionine), S-adenosyl-methionine (the first metabolite of methionine) and S-adenosylmethionine) (the demethylated product of S-adenosylmethionine) over 24h in 12 healthy subjects. 3. As well as the expected increase in homocysteine (from 8.0 +/- 1.3 to 32.6 +/- 10.3 mumol/l, mean +/- SD, P < 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 +/- 25.0 to 240.3 +/- 109.2 nmol/l, P < 0.001), which correlated well with homocysteine (r2 = 0.92, P < 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 +/- 7.2 to 13.1 +/- 2.9 nmol/l, P < 0.01), and gradually returned to baseline levels after 24h. No significant change over the time of measurement was found for S-adenosylhomocysteine. 4. The sequence of metabolic changes observed in this study strongly suggests that a change in either homocysteine or S-adenosylmethionine may cause a reduction in 5-methyltetrahydrofolate. This must be considered in evaluating the relationship between folate and homocysteine in vascular disease. The metabolic relationships illustrated in this study should be evaluated in the search for pathogenetic mechanisms of mild hyperhomocysteinaemia and vascular disease.

Adult↗
PubMed1996

An AFM investigation of the effects of acute hypoxia on mental rotation.

To determine if the stimulus identification stage of information processing is slowed by hypoxia, eight highly trained subjects performed a mental rotation task involving same or different responses to pairs of two-dimensional figures rotated in the picture plane. They breathed low oxygen mixtures adjusted to maintain arterial blood oxygen saturation at 64%. The results showed that hypoxia increased the intercept rather than the slope of the linear function relating reaction time to angle of rotation. According to Additive Factors Method logic, this result indicates that hypoxia does not slow stimulus identification. This is further evidence against the long-held view that hypoxia impairs information processing mechanisms throughout the system--the multiple loci hypothesis. The authors propose instead the early slowing hypothesis. According to this view, the slowing produced by hypoxia is highly specific to one or two early stages of visual processing, and this early slowing acts as a bottleneck to later processing.

Adult↗
PubMed1996

Defects in human methionine synthase in cblG patients.

Inborn errors resulting in isolated functional methionine synthase deficiency fall into two complementation groups, cblG and cblE. Using biochemical approaches we demonstrate that one cblG patient has greatly reduced levels of methionine synthase while in another, the enzyme is specifically impaired in the reductive activation cycle. The biochemical data suggested that low levels of methionine synthase activity in the first patient may result from mutations in the catalytic domains of the enzyme, reduced transcription, or generation of unstable message or protein. Using Northern analysis, we demonstrate that the molecular basis for the biochemical phenotype in this patient is associated with greatly diminished steady-state levels of methionine synthase mRNA. The biochemical data on the second patient cell line implicated mutations specific to reductive activation, a function that is housed in the C-terminal AdoMet-binding domain and the intermediate B12-binding domain, in the highly homologous bacterial enzyme. We have detected two mutations in a compound heterozygous state, one that results in conversion of a conserved proline (1173) to a leucine residue and the other a deletion of an isoleucine residue (881). The crystal structure of the C-terminal domain of the Escherichia coli MS predicts that the Pro to Leu mutation could disrupt activation since it is embedded in a sequence that makes direct contacts with the bound AdoMet. Deletion of isoleucine in the B12-binding domain would result in shortening of a beta-sheet. Our data provide the first evidence for mutations in the methionine synthase gene being culpable for the cblG phenotype. In addition, they suggest directly that mutations in methionine synthase can lead to elevated homocysteine, implicated both in neural tube defects and in cardiovascular diseases.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Low whole-blood S-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease.

Mild elevation of plasma homocysteine is an independent risk factor for vascular disease. We studied the role of 5-methyltetrahydrofolate (5-MTHF), the folate form directly involved in homocysteine metabolism, in contrast to previous studies, which used total folate measurements, in 70 coronary artery disease (CAD) patients and control subjects. We also measured S-adenosylmethionine (SAM), which controls the activity of critical enzymes of homocysteine metabolism. Fasting plasma total homocysteine was elevated (> 12.4 mumol/L for women, > 13.3 mumol/L for men) in 17% of patients, in accordance with earlier studies. These patients showed lower 5-MTHF (12.4 +/- 1.0 mumol/L, mean +/- SD) than control subjects (24.2 +/- 15.0, P < .001), and there was a clear correlation (multiple linear regression analysis: P = .002) of this relevant form of folate with homocysteine. However, 37% of the normohomocysteinemic patients also revealed similarly low 5-MTHF levels, suggesting that a decrease of 5-MTHF does not necessarily cause hyperhomocysteinemia. SAM was significantly decreased in patients (1.4 +/- 0.4 mumol/L) compared with control subjects (1.8 +/- 0.3, P < .001) but was not correlated to homocysteine or 5-MTHF. The correlation between homocysteine and 5-MTHF that was found in CAD patients but not in control subjects confirms the direct relationship between these compounds in vivo. The new finding of low SAM in patients demands further studies, since it might indicate that low levels pose risk and that SAM might be a protective factor against the development of CAD.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1995

Thrombomodulin and ristocetincofactor in homocystinuria: a study in two siblings.

Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often presents with vascular disorders, e.g. thromboembolic events. The measurement of vascular endothelial markers in plasma could help to assess endothelial damage. We determined von Willebrand factor (measured as Ristocetincofactor, RiCoF) and thrombomodulin (TM), two endothelial cell markers to our knowledge not measured systematically before in homocystinuria patients in a longitudinal study of two homocystinuric patients: Patient1 with thromboembolic disease and his asymptomatic sister, patient2. Before start of therapy in patient 1, TM and RiCoF levels both were increased. In patient 2 a moderately elevated RiCoF and a normal level of TM were found. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma, and complete normalization of RiCoF and TM levels in both patients. Thus, TM and RiCoF elevations demonstrate that CBS-def-HOCY leads to endothelial cell damage, which resolved under vitamin therapy in the patients studied.

Adult↗
PubMed1995

Biotinidase Km-variants: detection and detailed biochemical investigations.

We describe a simple method for the detection of biotinidase Km-variants and detailed biochemical investigations in 5 such patient. They were detected among 103 patients with plasma biotinidase activity which ranged from undetectable to 30% of the mean normal value. Two different types of biotinidase Km-variants were found. (1) In 3 infants biotinidase had a single 105-430-fold elevated Km for biocytin. Biotinidase showed very low activities (0.2-4% of the mean normal value) in the routine colorimetric assay and was not functional in vivo. Accordingly, these patients presented with classical clinical illness. (2) In two patients biotinidase showed biphasic kinetics indicating the presence of one component with a normal Km and reduced Vmax (1.7% and 12%), and another with 330- and 59-fold elevated Km, respectively. In these two patients, biotinidase proved to be at least partially functional in vivo. However, the first patient developed severe symptoms and biotin deficiency late, at the age of 10-15 years, and the second had marginal biotin deficiency at the age of 2 years but no clinical symptoms. Comparative studies revealed that both patients had more severe biotin deficiency than age-matched patients with similar levels of residual biotinidase activity and a single normal Km. Therefore, all patients with residual biotinidase activity should be evaluated for the presence of a Km-mutation, since such patients should be treated with biotin. These can easily be detected by including a second substrate concentration (1.5 mmol/L) in the routine colorimetric biotinidase assay which is performed with 0.15 mmol/L biotin. Increased activity with the higher substrate concentration indicates the presence of a Km-mutation. Detailed kinetic studies are needed to evaluate the distinct forms of Km-variants.

Amidohydrolases↗
PubMed1995

Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level.

Hyperhomocysteinemia occurs in approximately 30% of the patients with premature occlusive arterial disease (POAD). Some of these exhibit significantly reduced fibroblast cystathionine beta-synthase (CBS) activities, suggesting that they may be heterozygous for CBS deficiency. To test this possibility, we studied cDNA derived from four well characterized patients with POAD, exhibiting hyperhomocysteinemia and reduced CBS activities, from four normal controls, and from four obligatory heterozygotes for CBS deficiency. Lysates of individual colonies of E.coli, containing full-length PCR-amplification products in the expression vector, pKK388.1, were tested for CBS activity. cDNA from at least seven of the eight possible independent POAD alleles encoded catalytically active, stable CBS which exhibited normal response to both PLP and AdoMet. The sequences of all 3'-untranslated regions of all seven isolated POAD alleles were identical to the normal, 'wild-type' CBS sequences. The results of the expression studies were confirmed for one POAD patient by determining the full-length cDNA sequences for both alleles; these were entirely normal over the complete length of the cDNA. In contrast, the screening method correctly distinguished mutant from normal alleles in all four obligatory heterozygotes studied. We conclude that CBS mRNAs from POAD individuals are free from inactivating mutations, including all 33 previously identified in heterozygous carriers and homocystinuric patients.

Alleles↗
PubMed1995

Cardiomyopathy in respiratory chain disorders.

Disorders of mitochondrial oxidative phosphorylation may disturb cardiac energy metabolism and cause cardiomyopathy. Twenty one cases from the literature and one further patient with cardiomyopathy due to biochemically defined respiratory chain defects were reviewed for clinical course, morphology, and pathophysiological mechanisms of the cardiomyopathy. All cases showed concentric hypertrophy of the myocardium without an outflow tract obstruction. In most patients the cardiomyopathy was diagnosed early in infancy and showed rapid deterioration with death before the age of 2 years. Hypertrophy of the myocardium appears to result from swelling of the cardiomyocytes caused by accumulation of mitochondria and by morphologically abnormal megamitochondria.

Cardiomyopathy, Hypertrophic↗
PubMed1995

A comparison of visual and auditory reaction time and P300 latency thresholds to acute hypoxia.

To investigate the influence of stimulus modality on the slowing produced by hypoxia, thresholds were estimated using reaction time (RT) and the event-related brain potential P300. Six trained subjects responded to oddball light flashes or tone pips while breathing low-oxygen mixtures that were manipulated to produce arterial blood oxygen saturations (SaO2) ranging from 77-86%. Both RT and P300 were slowed in a dose-dependent manner. The threshold for slowing was independent of stimulus modality for both measures, and estimated to be in the range 81-82% SaO2. P300 amplitude dissociated from the response time measures by exhibiting an inverted-U dose-response function. We draw three conclusions from these results: a) the failure to observe a higher visual threshold for the response time measures is inconsistent with the traditional belief that audition is relatively insensitive to hypoxia; b) the equal sensitivity of P300 latency and RT to hypoxia implicates stimulus evaluation processes in slowing; and c) P300 amplitude may reflect the activity of physiological compensatory mechanisms to hypoxia.

Adult↗
PubMed1995

Dissociation of the behavioral and subjective components of nitrogen narcosis and diver adaptation.

We investigated adaptation to nitrogen narcosis by compressing 11 highly experienced divers in a hyperbaric chamber to the equivalent of 54.6 meters of seawater once a day for 5 consecutive days. The behavioral component of narcosis was assessed with a serial choice-reaction time (RT) task, and the subjective component with a global magnitude estimate. Supplementary magnitude estimates were obtained with adjectives describing work effectiveness and body sensations. The results showed that there was no adaptation on the RT task, although learning was evident. In contrast, the global estimate dissociated from RT and showed clear adaptation by Day 3. The work effectiveness adjectives followed RT and did not show adaptation. Some body sensation adjectives showed clear adaptation, but others did not. These results lead to the conclusion that the anecdotal reports of adaptation by divers can probably be attributed to the subjective rather than the behavioral component of narcosis. Dissociation of these components suggests mediation by different brain mechanisms, and it is speculated that the gamma-aminobutyric acidA/benzodiazepine receptor complex, which has been implicated in both the anesthetic and anxiolytic properties of agents such as nitrous oxide, may be involved.

Adaptation, Physiological↗
PubMed1994

Discriminating the effects of triazolam on stimulus and response processing by means of reaction time and P300 latency.

The benzodiazepines slow information processing and the sites of this slowing were mapped using the Additive Factors Method in combination with the P300 component of the event-related brain potential. It was assumed that P300 largely reflects the time to evaluate a stimulus while reaction time (RT) reflects this time plus the time to select and execute a response. Twelve subjects were administered 0.25 mg triazolam in a repeated measures single-blind design. A visual 80-20% oddball task was used in which stimulus intensity and signal quality were manipulated with accuracy of responding held constant at a high level. RT and EEG data were collected simultaneously and the P300 elicited by the low probability stimuli was measured on a single trial basis. Triazolam slowed RT (172 ms, P < 0.0003) more than P300 (88 ms, P < 0.0007), but both measures exhibited a drug x stimulus intensity interaction. RT also exhibited a drug x signal quality interaction but P300 did not. These results suggest that triazolam has selective effects on perceptual processing by slowing an early pre-processing stage but not a later feature extraction stage. In addition, the drug appears to slow some aspect of response processing. This evidence is taken as support for a multiple process rather than a general sedation view of benzodiazepine effects on stages of processing.

Adult↗