The Abnormality of Tryptophane Metabolism in Children with Mongolism

Abstract

There is evidence (Gershoff, Hegsted and Trulson, 1958; Jer6me, Lejeune and Turpin, 1960;O'Brien, Groshek and Streamer, 1960) that children with mongolism have a defect in tryptophane metabolism which is characterized primarily by a diminished urinary excretion of xanthurenic acid.The purpose of this study was to confirm this observation using more exact techniques and to attempt to specify the alteration in metabolism more precisely by comparing the effects of 1-tryptophane loading on the urinary excretion coefficients (,umols/ kg./7 hours) of both 5-hydroxy-3-indoleacetic acid and the kynurenine pathway metabolites of tryptophane in a group of children with mongolism and in a control group of non-mongoloid mentally retarded children.Methods Twenty-one children with mongolism, aged 9 to 16 years, and 19 non-mongoloid mental defectives of comparable age, sex and intelligence were studied. All the children were active, able to feed themselves and keep themselves clean. Both groups were in the same institution and received an identical diet. At the commencement of the test, fasting subjects voided and then drank 300 ml. of flavoured milk in which was suspended 100 ml./kg. body weight of 1-tryptophane. All urine was collected for seven hours after the tryptophane load, and, to ensure completeness, individual voidings were supervised by one or other of the investigators. This seven-hour collection period was chosen as being the longest period that could be properly monitored.A measured aliquot of urine was assayed for 5-hydroxy-3-indoleacetic acid (Udenfriend, Titus and Weissbach, 1955), N'-methylnicotinamide (Huff and Perlzweig, 1947;Asami, 1957), and 4-pyridoxic acid (Reddy, Reynolds and Price, 1958). Other metabolites of the kynurenine pathway were separated by two-dimensional paper chromatography and identified under ultraviolet light. These were then eluted and estimated either directly by their absorbance in the ultraviolet, or as azo compounds coupled with pyridine or naphthylethylenediamine (Coppini, Benassi and Montorsi, 1959;O'Brien and Ibbott, 1962a). The chromatographic methods were linear within the experimental range and recoveries for kynurenine, acetylkynurenine, kynurenic acid, hydroxykynurenine, xanthurenic acid and hydroxyanthranilic acid gave a mean value of 97-6% (82-5-104-7%) with a mean coefficient of variation of 7 9% (4-6-12 6%). Reproducibility, expressed also as a coefficient of variation, averaged 4-7% for standards and 5 9% for urine samples. These figures were shown to be slightly, but not significantly, better than those for column chromatography techniques (Satoh and Price, 1958) in the cases of kynurenic and xanthurenic acids.Because intravenous tryptophane loading was not permitted, fasting, one-and two-hour serum samples were obtained for estimation of the tryptophane levels. These were determined as the enol-borate complex after adsorption and elution from a Dowex 50 column (O'Brien and lbbott, 1962b).

Plasma amino acids in patients with senile dementia and in subjects with Down's syndrome at an age vulnerable to Alzheimer changes

“…The present study was undertaken to find if the changes in plasma amino acids seen in senile dementia occur also in Down's syndrome, while accepting that this is not a perfect model for Alzheimer's pathology, partly because Down's syndrome may be associated with malabsorption (Williams et al, 1985;O'Brien & Grosher 1986) and partly because the Alzheimer changes in Down's syndrome could have a different origin, yet share a final common pathway and resultant histopathology.…”

Platelet‐rich Plasma 5‐hydroxytryptamine, Urinary 5‐hydroxyindoleacetic Acid and Tryptophan Ingestion in Mongols

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Blood 5-hydroxytryptamine (5HT, serotonin) level in trisomic mongols has been found to be lower than in spastics (Paasonen and Kivalo, 1962) and lower than in healthy controls (Rosner, Ong, Paine and Mahanand, 1965;Tu and Zellweger, 1965;Berman, Justice and Hsia, 1965;Berman, Hulten and Lindsten, 1967; McCoy, Rostafinsky and Fishburn, 1968;Jerome and Kamoun, 1970;Boullin and O'Brien, 1971). Reasons for this have been quite unknown until now and results are still somewhat conflicting, although there have been several studies of the metabolism of tryptophan and 5HT in Down's syndrome (Gershoff, Hegsted and Trulson, 1958;Jerome, 1962;O'Brien and Groshek, 1962; Careddu, Tenconi and Sacchetti, 1963; McCoy and Chung, 1964; Vassella, Colombo, Gloor and Rossi, 1968;Jerome andKamoun, 1967 andBoullin and O'Brien, 1971).A relative deficiency and a possible change in the metabolism of pyridoxine were observed in mongolism (McCoy and Chung, 1964;Tu and Zellweger, 1965; McCoy, Colombini and Ebadi, 1969). Tu and Zellweger (1965) suggested, that this relative deficiency might depress the decarboxylation of 5-hydroxytryptophan (5HTP), where pyridoxine acts as a co-factor.

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Tryptophan Metabolism in Man *

“…also factors such as the adequacy of intestinal absorption of tryptophan, the age, sex, and nutrition of the subject (8), and the amount of tryptophan administered. Although abnormalities in tryptophan metabolism have been described in a number of disease states (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the significance of these observations has often been difficult to explain or understand. Part of this difficulty may be related to an inadequate assessment of these variables.…”