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Hydroxykynureninuria Arch Dis Child: first published as 10.1136/adc.39.205.250 on 1 June 1964. Downloaded from Arch. Dis. Childh., 1964, 39, 250. HYDROXYKYNURENINURIA A CASE OF ABNORMAL TRYPTOPHAN METABOLISM PROBABLY DUE TO A DEFICIENCY OF KYNURENINASE BY G. M. KOMROWER, VERA WILSON, J. R. CLAMP and R. G. WESTALL From the Research Unit, Royal Manchester Children's Hospital, and Medical Unit, University College Hospital Medical School, London (RECEIVED FOR PUBLICATION JANUARY 14, 1964) During the past decade the route by which tests. This was not due to pyridoxin deficiency, tryptophan is converted to nicotinamide has been and he concluded that this was an inherited trait. well studied, but the later stages of the conversion However, there has been no report concerning the have yet to be fully explained. This tryptophan- presence of large amounts of these substances in the nicotinamide transformation has been shown to urines of subjects without active disease who have occur in mammals (Rosen, Huff and Perlzweig, an adequate pyridoxin intake under normal dietary 1946) and later the formation of labelled nicotinic conditions. We describe here an individual who acid from C14-labelled tryptophan was demon- seems to show this abnormality. strated by Heidelberger, Abraham and Leprovsky (1949). Kotake and Nakayama (1941) and Case History copyright. Dalgliesh, Knox and Neuberger (1951) showed that, along this series of reactions, the conversion of R.R., the first and only child, was born at term on kynurenine to anthranilic acid and of 3-hydroxyky- July 3, 1952 following a normal pregnancy. The birth nurenine to 3-hydroxyanthranilic acid was, in each weight was 7 lb. 8 oz. (3402 g.), and following a breech the same extraction the baby was shocked and anoxic. However, instance, catalysed by enzyme, namely she responded quickly to oxygen therapy, fed well and kynureninase. Charconnet-Harding, Dalgliesh and regained her birth weight by the eighth day. She was Neuberger (1953) found that in addition to noted to be short (length 17j in. (44 cm.), but radiological http://adc.bmj.com/ kynurenine, kynurenic acid and xanthurenic acid, examination of the skeleton was said to be normal. She 3-hydroxykynurenine was excreted on administra- was discharged home and readmitted after 14 days tion of tryptophan to rats fed on a low pyridoxin because of, (i) reddening of the buttocks with some diet. desquamation; (ii) mild stomatitis and gingivitis; and Many workers since have demonstrated these (iii) loose stools with occasional flecks of blood. tryptophan derivatives in the urines of pyridoxyl- On examination she weighed 7 lb. 8 oz. (3402 g.) and individuals was pyrexial. There was marked stomatitis and cervical deficient or pyridoxyl-dependent (Bessey, adenitis. Buttocks were reddened. She was pale. Full Adam and Hansen, 1957; Molony and Parmelee, blood count revealed red blood cells 2- 58 million. on September 24, 2021 by guest. Protected 1954; Coursin, 1961; Hunt, Stokes, McCrory and Hb 7-7 g./100 ml., colour index 1 -06, white blood cells Stroud, 1954; Scriver, 1960; O'Brien and Jensen, 3,800 per c.mm., neutrophils 27%, eosinophils 8%, 1963) usually following a tryptophan load. In lymphocytes 59%, monocytes 6%. Blood Group B, addition xanthurenic acid has been found in the Rhesus negative. Coombs test, negative. urine of uncontrolled diabetics (Kotake and Tani, Treatment was started with chlortetracycline, vitamin 1953) and in tropical sprue (Sigler, Sheehy, Santini C and 'becosym'. The state of the mouth and buttocks and Rubini, 1962) and 3-hydroxykynurenine in cases improved but the child remained pyrexial and anaemic. Hepatosplenomegaly was not noted. On August 7, 1952 of active tuberculosis, fever of various kinds and in she was transferred to Royal Manchester Children's leukaemia, multiple myeloma lymphosarcoma and Hospital. Her weight was 7 lb. 9 oz. (3430 g.); Hodgkin's disease (Musajo, Benassi and Parpajola, temperature 1020 F. (390 C.). There was marked 1956). Further, Knapp (1962) has reported that a stomatitis, and the buttocks were reddened, with some number of patients excrete an increased amount of excoriation. The liver and spleen were felt 1 in. (2 *5 cm.) these tryptophan metabolites after tryptophan load below the respective costal margins. There was a slight 250 Arch Dis Child: first published as 10.1136/adc.39.205.250 on 1 June 1964. Downloaded from HYDROXYKYNURENINURIA 251 kyphoscoliosis, and shortness of the upper arms and preparation, 'Prosol', cereal and a vitamin preparation, thighs relative to the size of the trunk and rest of the 'Abidec'. limbs was noted. During 1953 she made slow but steady progress. The liver and spleen diminished in size and could no longer be Investigations. Hb 44% (6-5 g./100 ml.), white felt, although on re-examination the right femoral caput blood cells 9,200, polymorphs 13%, lymphocytes 74%, epiphysis was still less well developed than the left. eosinophils 7%, monocytes 5%, reticulocytes 1%; All the milestones were reached late, and in July 1956 at Coombs, direct and indirect, negative; some increase of the age of 4 years her vocabulary was poor, although she fragility, 25% haemolysis at 0 -6 N saline. Iliac crest understood everything that was said to her. She had marrow showed a picture of marked normoblastic just begun to play with other children, and bowel and hyperplasia. Urobilin was present in slight excess. bladder training were satisfactory. Liver function tests showed no evidence of parenchymal She continued to progress with adequate radiological cell disturbance. ossification of the head of the right femur, and she was This was thought to be an acquired haemolytic next seen in July 1960 at the age of 8 years 2 months anaemia, as the Coombs test on two further occasions when she was brought because the school authorities said was positive, and 100 ml. of compatible blood was given. she was mentally retarded. On examination her general Marked accentuation of jaundice was noted with an condition was good, there was no shortening of the right increase of the hepatosplenomegaly following the leg, but there was a conductive deafness in the left ear. transfusion. The I.Q. was 78 (verbal scale I.Q. 96: performance scale The pyrexia was maintained and after one week the I.Q. 64). Further radiological examination showed a stools became very frequent and the anaemia more definite improvement in the outline and internal bony pronounced. structure of the head and neck of the right femur. On August 16, 1952, a further transfusion was given; Development as to size and number ofcarpal centres was once again there was an increase of jaundice with some above the average (centre for pisiform forming). further enlargement of the liver. Detailed investigations were undertaken and will be Glucose in quantity and vitamin B complex were given described later. as therapy. Two days later a left otorrhoea was noted In September 1962 at the age of 10 years 2 months and appropriate parenteral and local antibiotic therapy nicotinic acid ('niacin') 10 mg. was prescribed in addition was started. From this point the jaundice began to fade to pyridoxin 50 mg. daily. In November 1963 at 11 years 4 months she was in but the hepatosplenomegaly persisted. The diarrhoea copyright. was still present, and there was an obvious proctitis. excellent health, having made an appreciable gain in The ear condition began to clear but on September 7, an height and weight (Fig. 1) during the previous 18 months. appreciable amount of pus was passed per rectum She was heavily built and secondary sexual characteristics followed later by some blood. were appearing (Fig. 2). The progress at school had Following a further transfusion the anaemia improved, been good although she was still one year behind her the hepatosplenomegaly diminished, the left ear became age-group. She had suffered from migrainous headaches dry, but blood and pus continued to be passed per rectum. before the introduction of nicotinic acid therapy; since that time she had had only one headache, when the Esch. coli and Staph. albus were grown from the rectal http://adc.bmj.com/ swab. On radiological investigation barium enema and vitamins had been omitted for four days. Her mother barium meal examinations did not reveal any abnormal- and grandmother both suffered in a similar manner ities of the intestine or colon, but developmental defects although her mother had been very well following the of the lower dorsal and first lumbar vertebrae and of the introduction of daily 'Becosym forte' (pyridoxin 20 mg.; eighth, ninth, eleventh and twelfth left ribs were noted. niacin 100 mg.). As the red cell fragility had been The long bones were seen to be short and the development abnormal in infancy this investigation was repeated; this of the left leg epiphysial centres somewhat in advance of had returned to normal. the right. A diagnosis of 'Brailsford-Morquio' was suggested. Methods on September 24, 2021 by guest. Protected In October a laparotomy was performed when the Urine Collection. Aliquots of 24-hour collections pelvic colon was found to be inflamed. Chloramphenicol were used for analysis except after the tryptophan loading 100 mg. eight-hourly was given for 15 days, and local tests when four consecutive three-hourly specimens were chinioform enemata were started and continued for two obtained followed by a final collection between 12 and 24 months. The fever settled slowly, the diarrhoea abated, hours. the proctitis and peri-anal redness improved. The blood count on December 17 was red blood cells 3 -8 million; Paper Chromatography. Two-way paper chromato- Hb 72%; white blood cells 9,400: polymorphs 45%; grams of the urinary tryptophan derivatives were done by lymphocytes 42%; monocytes 9%. following the method of Smith (1958) using n-butanol, Repeated blood cultures taken during the illness had acetic acid and water (120; 30; 50 parts by volume) as the been negative and a mesenteric gland taken at biopsy did first solvent and 20% potassium chloride as second not reveal any particular pathology.
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