John A. Anderson

Tryptophan Metabolism in Man

The amino acid tryptophan is unique because it contains the indole nucleus and because it is metabolized in man through several different biochemical pathways to a number of specific products. It is the precursor of serotonin and 5-hydroxyindoleacetic acid. In addition, after cleavage of the indole ring, it may be metabolized by way of the kynurenine pathway to 3-hydroxyanthranilic acid and ultimately to nicotinamide. In mammalian liver the benzene ring is oxidized and metabolized through a number of intermediate reactions to glutarate, acetate, and carbon dioxide (1, 2). Tryptophan is also the precursor of indolic acids, such as 3-indoleacetic acid. In man this compound is formed both by tissue enzymes and by bacteria in the gut (3). In the intestinal tract, bacteria that contain tryptophanase (4) reductively cleave the side chain of tryptophan and form indole, which is absorbed, conjugated in the liver, and excreted as indican (sulfated potassium ester of indoxyl). In addition to the various reactions involving the indole ring or side chain, tryptophan, like other amino acids, is incorporated into protein. These pathways are schematically shown in Figure 1. The many different enzyme systems and important cofactors, such as pyridoxal phosphate, that take part in these reactions have been ably reviewed (5-7) and will not be discussed here. In the investigation of tryptophan metabolism in man, a number of variables must be considered. These include not only these enzymes and cofactors, but

The characteristic dentition of incontinentia pigmenti

Summary Incontinentia pigmenti (Bloch-Sulzberger syndrome) has a characteristic dentition that may aid in its diagnosis. The changes are: marked hypodontia, delayed eruption, and conical crown form of both deciduous and permanent dentitions. Changes similar to those observed in the anhidrotic form of ectodermal dysplasia strongly suggest that incontinentia pigmenti is related.

L-tryptophan metabolism in phenylketonuria†

A disturbance of the intestinal transport of L-tryptophan and L-tyrosine secondary to the high blood phenylalanine content has been suggested. The L-tryptophan metabolic abnormalities observed in untreated phenylketonuria appear to be due to a transport defect of this amino acid. Six phenylketonuric subjects were studied before and after a low phenylalanine diet. Hyperphenylalaninemia was associated with striking limitation in absorption of tryptophan and tyrosine as reflected by significantly low fasting plasma tryptophan values, limitation in the peak plasma tryptophan response to the oral load, increased fecal tryptophan and tyrosine content, and increased fecal and urinary indoles. Following dietary correction of plasma phenylalanine concentrations, all these abnormalities returned to normal when compared with responses in normal children.

Identification of heterozygotes with phenylketonuria on basis of blood tyrosine responses

The differences in the responses of the tyrosine concentration in the serum to a two dose oral loading test with l -phenylalanine provided good separation of heterozygotes with phenylketonuria from control subjects. Determination of a discriminating factor by a combination of either the fasting, one, and two hour tyrosine values, or only the one and two hour values, permitted separation of the two groups with approximately a 5 per cent error. The discriminating values so derived gave an expression of differences in the rate of formation of tyrosine from l -phenylalanine within the two hour period and appeared to be a critical method of measuring the presence of a partial gene-enzyme deficiency.

Atypical phenylketonuric heterozygote. Deficiency in phenylalanine hydroxylase and transaminase activity.

A child with an elevated serum level of phenylalanine, a typical phenylketonuria phenylalanine tolerance test, an absence of increased urinary concentrations of phenylketones, ortho- and parahydroxyphenyl acids, and phenolic acids, as well as no abnormality in urinary excretion of 5-hydroxyindoleacetic acid or in indole-3-acetic acid is reported. It appears that this child has marked limitation in phenylalanine transaminase activity and, as a consequence, the characteristic associated biochemical abnormalities related to limited activity of this enzyme were not expressed and could not be evoked.

Acute pulmonary coccidioidomycosis in children

Observations of the clinical features of acute pulmonary coccidioidomycosis in 73 children have indicated the importance of erythema multiforme and chest pain at the onset. The variability of the clinical course and roentgenographic manifestations is described.

Twelve years of clinical experience with phenylketonuria. A statistical evaluation of symptoms, growth, mental development, electroencephalographic records, serum phenylalanine levels, and results of dietary management.

SINCE THE INTRODUCTION of dietary treatment to modify or prevent severe mental retardation in phenylketonurics, there have been relatively few published reports on the value of this form of therapy for a large number of phenylketonurics treated over a long period of time.1-13 The limited number of treated phenylketonurics available to each investigator, as well as the absence of comparable untreated phenylketonurics, does not admit of statistical evaluation of the dietary treatment. The dietary treatment is also difficult to evaluate because of the wide variation14J5 in the biochemical and clinical expression of the disease. In some studies, children having transitory16 or relatively permanent elevations17 in the serum-phenylalanine level have been equated with children having classical phenylketonuria and may have been included in the treated groups. While the value of the dietary treatment has not been conclusively established, certain data suggest that dietary treatment begun within the first months of lift? and properly monitored is of value in preventing severe mental retardation in some phenylketonurics. However, dietary treatment may also lead to cutaneous changes,

Effects of Desoxycorticosterone Acetate on Water and Electrolyte Content of Brain and Other Tissues

In a previous study on the antagonistic action between pitressin and desoxycorticosterone acetate in epileptic subjects, the authors 1 found the latter substance to have a striking anti-convulsive effect for both spontaneously occurring and pitressin-induced seizures. The principal experimental subject involved- in that investigation, a young man with extremely severe epilepsy, has remained essentially free from convulsive attacks during the intervening 3 years while continuing to receive this synthetic hormone sublingually or by subcutaneous pellet implantation. The present experimental study was undertaken with the hope of obtaining some information regarding the physiological or pharmacological mechanism responsible for this effect. Our immediate objective was to determine the effects of the hormone on the water and electrolyte content of the brain tissue of normal animals. It has been abundantly demonstrated by Darrow and Miller 2 , 3 , and by Ferrebee and co-workers 4 that the potassium content of skeletal muscle, as well as that of blood plasma, is greatly reduced and the sodium content is somewhat increased by daily injections of comparatively large doses of desoxycorticosterone acetate. Heart muscle and liver showed much less, or (in some animals) no alteration. 3 Data regarding the brain were not reported by these authors. In the present study, changes in skeletal muscle, liver and heart muscle were determined for the purpose of comparison. Eighty young hooded rats (initial weights, 150 to 200 g each) maintained continuously from the time of weaning and throughout the experiments on a standard rat diet containing 0.605 g of K, 0.565 g of Na, and 1.155 g of CI per 100 g, were divided into two equal groups.

Failure to detect subtle neurotropism of live, attenuated measles virus vaccine

A multidisciplinary study of a small group of institutionalized children has failed to provide any evidence of virus neurotropism or of even subtle neurophysiologic dysfunction following inoculation with live, attenuated measles virus. This conclusion was based on the absence of evidence for (a) persistent alteration of circadian temperature rhythm, (b) a change in quantified encephalographic electrical output, (c) spinal fluid pleocytosis or elevation of protein content, (d) an altered hematoencephalic barrier, or (e) dissemination of virus to the central nervous system.

Tryptophan Oxidation in Phenylketonuria

Extract: Tryptophan oxidation was evaluated in 6 institutionalized phenylketonuric subjects (age range 5–13 years) by measuring the urinary excretion of oxidation metabolites following administration of L-tryptophan loads by mouth. Observations were made when subjects were on a general diet, a low-phenylalanine diet and a low-phenylalanine diet containing added L-phenylalanine. At some time during each dietary regime, the subjects also received tryptophan by mouth, 100 mg/kg body weight. Measurement was made in urine of: 1. 3-hydroxykynurenine; 2. kynurenine; 3. acetyl kynurenine; 4.3-hydroxyanthranilic acid; 5. xanthurenic acid; 6. kynurenic acid; 7. anthranilic acid; 8.3-indole-acetic acid; 9. o-hydroxyphenylacetic acid; and 10. phenylpyruvic acid. Excretion of tryptophan-kynurenine metabolites (products 1–9) amounted to 3.78 μmoles/kg/24 h and was similar to that of control subjects while on all diets. With tryptophan loading on normal diets, excretion of metabolic products was lower than for control subjects. With tryptophan loading on low-phenylalanine diets, the excretion of tryptophan metabolites was 2–3 times higher than the mean value of 22.7 μmoles/kg/24 h observed in normal subjects. The response to loading when the diet contained added phenylalanine was variable, since two patients excreted normal amounts of metabolites and three excreted amounts several times greater than the controls. Excretion of indole and 3-indoleacetic acid was abnormally elevated with and without tryptophan loading on normal diets and when phenylalanine was added to the low-phenylalanine diets. Values in μmoles/kg/24 h were: 3-indoleacetic acid 1.7 (normal); 2.5–9.4 (PKU); indican 6.24 (normal); 14.9–24.6 (PKU).Speculation: Limited metabolism of tryptophan may be of importance to central nervous system development and function in certain phenylketonuric children. Malabsorption of tryptophan coupled with an inhibition of the tryptophan-kynurenine synthesis pathway for nicotinic acid could deprive the central nervous system of important cofactors essential to central nervous system metabolism. The subtle effects of secondary disturbances on enzymatic pathways for tryptophan, tyrosine and other amino acids may be more important than the direct influence of the metabolites of phenylalanine on the central nervous system in phenylketonuric subjects.