Hydroxykynureninuria: A case of Abnormal Tryptophan Metabolism Probably Due to a Deficiency of Kynureninase

During the past decade the route by which tryptophan is converted to nicotinamide has been well studied, but the later stages of the conversion have yet to be fully explained.This tryptophannicotinamide transformation has been shown to occur in mammals (Rosen, Huff and Perlzweig, 1946) and later the formation of labelled nicotinic acid from C14-labelled tryptophan was demon- strated by Heidelberger, Abraham and Leprovsky (1949).Kotake and Nakayama (1941) and Dalgliesh, Knox and Neuberger (1951) showed that, along this series of reactions, the conversion of kynurenine to anthranilic acid and of 3-hydroxykynurenine to 3-hydroxyanthranilic acid was, in each instance, catalysed by the same enzyme, namely kynureninase.Charconnet-Harding, Dalgliesh and Neuberger (1953) found that in addition to kynurenine, kynurenic acid and xanthurenic acid, 3-hydroxykynurenine was excreted on administra- tion of tryptophan to rats fed on a low pyridoxin diet.Many workers since have demonstrated these tryptophan derivatives in the urines of pyridoxyldeficient or pyridoxyl-dependent individuals (Bessey, Adam and Hansen, 1957; Molony and Parmelee, 1954; Coursin, 1961; Hunt, Stokes, McCrory and Stroud, 1954; Scriver, 1960; O'Brien and Jensen, 1963) usually following a tryptophan load.In addition xanthurenic acid has been found in the urine of uncontrolled diabetics (Kotake and Tani, 1953) and in tropical sprue (Sigler, Sheehy, Santini and Rubini, 1962) and 3-hydroxykynurenine in cases of active tuberculosis, fever of various kinds and in leukaemia, multiple myeloma lymphosarcoma and Hodgkin's disease (Musajo, Benassi and Parpajola, 1956).Further, Knapp (1962) has reported that a number of patients excrete an increased amount of these tryptophan metabolites after tryptophan load tests.This was not due to pyridoxin deficiency, and he concluded that this was an inherited trait.However, there has been no report concerning the presence of large amounts of these substances in the urines of subjects without active disease who have an adequate pyridoxin intake under normal dietary conditions.We describe here an individual who seems to show this abnormality.Case History R.R., the first and only child, was born at term on July 3, 1952 following a normal pregnancy.The birth weight was 7 lb.8 oz.(3402 g.), and following a breech extraction the baby was shocked and anoxic.However, she responded quickly to oxygen therapy, fed well and regained her birth weight by the eighth day.She was noted to be short (length 17j in.(44 cm.), but radiological examination of the skeleton was said to be normal.She was discharged home and readmitted after 14 days because of, (i) reddening of the buttocks with some desquamation; (ii) mild stomatitis and gingivitis; and (iii) loose stools with occasional flecks of blood.On examination she weighed 7 lb.8 oz.(3402 g.) and was pyrexial.There was marked stomatitis and cervical adenitis.Buttocks were reddened.She was pale.Full blood count revealed red blood cells 2-58 million.Hb 7-7 g./100 ml., colour index 1 -06, white blood cells 3,800 per c.mm., neutrophils 27%, eosinophils 8%, lymphocytes 59%, monocytes 6%.Blood Group B, Rhesus negative.Coombs test, negative.Treatment was started with chlortetracycline, vitamin C and 'becosym'.The state of the mouth and buttocks improved but the child remained pyrexial and anaemic.Hepatosplenomegaly was not noted.On August 7, 1952 she was transferred to Royal Manchester Children's Hospital.Her weight was 7 lb.9 oz.(3430 g.); temperature 1020 F. (390 C.).There was marked stomatitis, and the buttocks were reddened, with some excoriation.The liver and spleen were felt 1 in.(2 *5 cm.) below the respective costal margins.There was a slight 250