hartnupdisease in psychiatric practice: clinical …total amino-acid nitrogen was determined by...

J. Neurol. Neurosurg. Psychiat., 1960, 23, 40.

HARTNUP DISEASE IN PSYCHIATRIC PRACTICE:CLINICAL AND BIOCHEMICAL FEATURES OF THREE CASES

BY

L. A. HERSOV* and R. RODNIGHTFrom the Maudsley Hospital, London

In a previous paper the case history was given ofa 10-year-old boy admitted to hospital for apsychotic illness associated with a photosensitiveskin rash (Hersov, 1955). The condition resembledclassical pellagra, and although no dietary reasonfor a vitamin deficiency was apparent, a goodresponse was obtained to treatment with nicotin-amide. Biochemical investigations revealed grossand persistent indicanuria and it was suggested byRodnight and Mcllwain (1955), who studied thisaspect of the illness, that the nicotinamide deficiencymight be due to a diversion of trytophan from itsnormal route of nicotinamide formation into that ofindican formation.

Shortly after the publication of these papers wewere approached by Professor C. E. Dent, whoexpressed interest in the patient and with whose helpwe were able to show that the boy was an instanceof Hartnup disease, the hereditary pellagra-likedisorder later reported in detail by Baron, Dent,Harris, Hart, and Jepson (1956). The syndromedescribed by these workers occurred in four out ofeight siblings of a marriage between first cousins andwas characterized by attacks of dermatitis andcerebellar ataxia; it was also claimed that thecondition was probably associated with progressivemental deterioration. Well-defined biochemicalabnormalities were present in the affected siblings,consisting of a constant renal aminoaciduria ofdistinctive pattern and a high excretion of indicanand other abnormal tryptophan metabolites. Ourpatient was shown to have an aminoaciduria ofexactly the same pattern, and although his clinicalsymptoms were in some respects different, there is nodoubt that he has the same basic disorder.We were stimulated by this observation to search

for further cases of Hartnup disease amongstpsychiatric patients. A female patient with similarsymptoms, kindly brought to our notice by Dr.Denis Leigh, was then found to have the biochemical

abnormality and examination of her family revealedan affected sister. The present paper describes thefollow-up of our original case for six years, togetherwith as much information on his family as it hasbeen possible to obtain, and the clinical and bio-chemical features of the second family. A pre-liminary report of some of the biochemical data hasalready been given (Rodnight, 1959a).

Case ReportsFamily A.-This is the family of the boy (M.H.) whose

first attack of Hartnup disease has already been describedby one of us (Hersov, 1955). The parents are not related.The incidence of amino-aciduria in the family is given inTable I. M.H. remains the only affected member, but ithas unfortunately been impossible to test the father (whodeserted some years ago) and a brother on militaryservice in the Far East. Further relatives have beensought without success.M.H. was admitted to the Children's Department of

the Maudsley Hospital in May, 1953, and discharged freeof symptoms in July of that year. Shortly afterwards thefamily moved to the north of England and contact withthe patient has been maintained through his schoolmedical officer and general practitioner. He ceasedtaking extra nicotinamide (prescribed on discharge) inOctober, 1955, and apart from a short spell of diarrhoeain the summer of 1954 and a transient skin rash in thespring of 1957, he has remained in good health. Hecompleted schooling at a secondary modern schoolwithout difficulty and is now apprenticed to a transportcorporation as a mechanic. The last report we had fromhis general practitioner (Dr. C. Potts) was in April, 1958,when no -skin lesions or neurological or psychiatricabnormalities were found.

Family B.-The parents are not related and there arethree daughters; the incidence of aminoaciduria isshown in Table I. The second daughter (E.) was firsttreated at the age of 18 years in 1949 by Dr. Denis Leighfor a psychiatric disorder associated with pellargrous skinlesions. Following publication of the paper by Baronet al. (1956) we tested her urine for amino-acids and foundher to be a case of Hartnup disease. Investigation of herfamily then showed that the eldest sister (J.) was alsosuffering from the disease, but there were no otheraffected members.

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* Present address: Child Guidance Training Centre, OsnaburghStreet, London.

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HARTNUP DISEASE IN PSYCHIATRIC PRACTICE

TABLE IINCIDENCE OF AMINO-ACIDURIA IN THE FAMILIES

Subject Age (years) Aminoaciduria

Family A - NFatner Not testedMother - AbsentM., female 28 AbsentR., male 26 Not testedS., female 23 AbsentM., male 16 Present

Family BFather AbsentMother ii AbsentJ., female 29 PresentE., female 27 PresentB., female 26 Absent

E.-The patient is now a married woman of 27 years.She was a healthy child apart from enuresis and tensionhabits which ceased at the age of 6 years. Her parentsnoticed from an early age that her skin would easilyredden and "peel" after exposure to sunlight. A severeattack occurred during a summer holiday when she was8 years old, the exposed areas of her body becoming red,painful, and later dark and scaly. There was anothersevere recurrence of the same skin lesions in the summerof 1948, the year before her admission to hospital.She was a rather timid, dependent child, attended a

central school, and was generally average in class with nobehaviour problems. She began work as a duplicatingmachine operator and continued in this occupation untilshe fell ill. At work she was popular, sociable, able, andeasy to supervise.

In October, 1948, she gradually experienced weaknessand stiffness in the lower limbs and on several occasions"collapsed" while walking and had to be assisted. Shewas able to continue work until February, 1949, when shecomplained of giddiness and double vision. This wasfollowed by complaints of recurrent feelings of stiffnessin the back and legs, which felt numb and tremulous afterexertion. She gave up work, but failed to improve.In April, 1949, she became severely depressed withsuicidal preoccupation and complaints of inability tofeel properly, and was admitted to the Maudsley Hospital.

Physical examination showed a fair-skinned, well-nourished girl (7 st. 7 lb.) with no skin lesions or ab-normality in the central nervous system apart from briskreflexes. All other systems were normal. She wasuntidy in appearance, depressed, apprehensive, tense andtearful, expressing suicidal ideas. She described severeand persistent feelings of depersonalization. Nohallucinations or delusions were elicited; orientation,concentration, and memory were unimpaired. Her stateshowed no change during the following three weeks: sheremained depressed and depersonalized, slept poorly, anddid not participate in ward activities, complaining ofstiffness and weakness in her limbs; at times she re-quired assistance when walking. Then, after exposureto sunlight, she developed a severe erythema of theexposed skin areas, together with an exacerbation of thedepression and depersonalization. No abnormality ofporphyrin metabolism was found in the urine, and herhistory and clinical picture led to a diagnosis of pellagra.Treatment with oral nicotinic acid (200 mg. daily)

resulted in the patient becoming markedly more cheerfuland active after 72 hours, followed by a decrease in thedepression and depersonalization. Within a week theskin lesions had returned to normal, and she was alsofree of psychiatric symptoms and somatic complaints.Prolonged exposure to sunlight then had no furtherharmful effect and she was discharged home fullyrecovered in July, 1949, after three months in hospital.The patient has been followed up as an out-patient over

the past 10 years. In May, 1950, she suffered from weeklyfainting attacks which came on without warning andlasted one or two minutes. There was no tongue biting,incontinence, or muscular spasms, and no drowsiness orconfusion followed the attacks. Enquiry revealed nohistory of previous epileptic attacks and no family historyof epilepsy. However, an electroencephalogram at thistime showed a number of non-specific anomalies atvarying frequencies of photic stimulation; coincidentalinjection of "metrazol" elicited a short burst of bilaterallysynchronous 3 per second spike and wave. The faintingattacks ceased with the administration of nicotinic acid(100 mg. daily). The patient remained well throughoutthe summer of that year and did not develop any skinlesions. Nicotinic acid was discontinued in October,1950.

In June, 1951, she had a similar fainting attack on oneoccasion, but again with no skin lesions or other symp-toms apart from irregular menstrual periods. Nicotinicacid was again prescribed and continued throughout thewinter. In the summer of 1952 she again had faintingattacks once a week for four weeks, but they ceased when"phenytoin" (grains thrice daily 1-5) and nicotinic acid(75 mg. daily) were given.

In June, 1953, the patient developed a sore tongue,angular stomatitis, and an erythematous scaly dermatitisof the exposed areas of the face and hands. There wereno complaints of fainting, depression, or depersonaliza-tion and the skin lesions responded rapidly to treatmentwith nicotinic acid.

Since then the patient has remained free of symptomsapart from mild anxiety and tension lasting a few monthsand related to marital difficulties. A neurological andpsychiatric examination in November, 1958, showed noabnormality. On this occasion psychological tests werealso carried out using the Wechsler intelligence scalewith the following results: full-scale I.Q., 95; verbalI.Q., 102; performance I.Q., 88. The patient is now inregular employment as a shop assistant.J.-The patient, a single woman of 29 years, is an

experienced typist holding a responsible position. Sheis a reticent, unassertive person with few friends andlimited interests. When 8 years old she suffered fromsevere osteomyelitis of the left leg, requiring operativetreatment, 18 months in hospital, and a caliper until shewas 16 years old. While convalescing from the operationshe remembers developing severe sunburn when exposedto the sun, requiring treatment with lotions and protectivemasks. Because of this liability to sunburn she eventuallyhad to be confined indoors. Since then she has beencareful to avoid excessive exposure to direct sunlight andprotects her skin with lotions. This symptom has notreappeared.

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L. A. HERSOV AND R. RODNIGHT

In 1948, at the age of 18 years, she was referred to themedical out-patient department of a general hospital for"6collapsing attacks" and backache. The symptoms were

of sudden onset and increased in severity over a periodof six months. After the "collapsing attacks" her legswould feel stiff and weak, and she would be unable toresume walking without a period of rest. During thesetimes she was also unusually tense, anxious, tearful, andirritable; she was unable to work. She was referred to a

psychiatrist, who made a diagnosis of "anxiety state" andprescribed a holiday of four weeks, during which hersymptoms disappeared completely. She has remainedwell since with no further symptoms. She was lastexamined at the Maudsley Hospital in November, 1958,when no neurological or psychiatric abnormalities were

found. An electroencephalogram at this time, however,showed i generalized abnormality with an excess ofcentral theta rhythm, but no specific epileptic features.Psychological testing on the Wechsler intelligence scalegave an I.Q. of 114.

Investigation of Family.-The father, aged 63 years,has been treated in the past for a duodenal ulcer but hasno history of skin lesions, or of neurological or psy-chiatric illnesses. The mother, aged 63 years, is a normaland healthy person. Both parents come from largefamilies, the majority of whose members have emigratedor cannot be traced.The youngest daughter (B.) is a single girl (26 years)

of a healthy, stable personality and above averageintelligence (Wechsler intelligence scale I.Q. 118). Thereis nothing unusual in her medical history. Two maternalnieces are backward children: the older is feeble-minded(I.Q. 60), but it has not been possible to test her urine;the younger is an imbecile and has been tested for amino-aciduria with a negative result.

Biochemical MethodsPaper Chromatography.-Two-dimensional paper

chromatography was clarried out on 9 x 9 in. squares ofWhatman No. 20 paper in the apparatus described byRodnight and Aves (1958).Urinary Amino-acids.-The determinations were made

by paper chromatography. Urine specimens were

electrolytically desalted and a series of two-dimensionalchromatograms were prepared using volumes of urinecontaining from 10 to 75 ,ug. nitrogen, in parallel withan appropriate range of standards. The solvents usedwere mixtures of butanol and acetic acid and phenol andammonia (Smith, 1958). Amino-acids were revealed byninhydrin and the intensities of the spots matched visuallyagainst the standards after storing the papers in the darkfor 24 hours. Several determinations at different levelswere made for each specimen and the maximum range oferror estimated as 25 %. Tryptophan was measuredseparately by a method given below. Total amino-acidnitrogen was determined by formol titration; sincedesalted samples were used no correction for urinaryammonia was required.

Urinary Indoles.-Indole chromatograms of freshurine specimens were prepared according to Rodnightand Aves (1958). Tryptophan was separated on de-

activated charcoal (Asatoor and Dalgliesh, 1956) anddetermined on two-dimensional chromatograms by visualcomparison with a range of standards. Serotonin andtryptamine were determined by the method of Rodnight(1956), except that the "amberlite" resin CG-50 was usedin place of "zeo-karb" 226 and the final estimations were

made on two-dimensional chromatograms. Indole acidswere determined by a chromatographic method describedelsewhere (Rodnight, 1959b). Indican was determinedaccording to Sharlit (1933).Whole blood indoles were examined by an acetone

extraction procedure described elsewhere (Rodnight,1959b).Urinary Kynurenic Acid and Xanthurenic Acid.-The

fluorometric method of Satoh and Price (1958) was used.Fluorescence was measured in a Locarte fluorometerusing the following filters for the primary and secondarysides of the instrument respectively.

Kynurenic Acid.-OX7 (Chance Bros.); LF3 (LocarteCo.).

Xanthurenic Acid.-OVI; GR2 and OY3 (all ChanceBros.).

Recovery ofthese substances added to urine ranged from65 to 90 %; internal standards were therefore used in eachestimation and the results quoted are corrected for losses.

Results of Biochemical InvestigationAminoaciduria.-The incidence of this in the two

families has already been given (Table I). Theaffected members in both families have been testedat approximately yearly intervals over a period ofsix years in the case of M. in family A, and overthree years for cases E. and J. in family B. Thehighly distinctive pattern of aminoaciduria waspresent on each occasion, and only minor differencescould be discerned between the subjects by visualinspection of the chromatograms.

In order to determine the magnitude of the loss ofamino-acids in our cases, estimates were made ofthe daily output of total amino-acid nitrogen andof the individual amino-acids in family B (Table II).

DAILY URINARY

TABLE II

EXCRETION OF AMINO-ACIDS INFAMILY B

Amino-acid J. E. B.

Alanine 650 500 50Asparagine 500 330 Not detectedAspartic acid Not detected 160 Not detectedGlutamic acid 430 40 Not detectedGlutamine 3,200 2,500 320Glycine 650 1,000 150Histidine 650 500 430Leucine 550 330 Not detectedIaoleucine JLysine 430 500 Not detectedPhenylalanine 210 250 Not detectedSerine 1,300 1,000 100Threonine 500 500 Not detectedTryptophan 40 40 15Tyrosine 500 330 30Valine 650 330 Not detectedTotal amino-acid N 1,290 1,099 151

Results expressed in mg. per 24 hours.

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Amino-acid excretion in subjects J. and E. exceededthat in the normal sister B. by a factor of nearly 10,and variable increases were found in all the amino-acids, with the exception of histidine, where thedifference lay within the error of the method.Especially notable is the excretion in the affectedcases of 2 to 3 g./day of glutamine and over 1 g. ofserine. With minor differences, therefore, theurinary amino-acid pattern in these cases closelyresembles that described by Baron et al. (1956) andEvered (1956) in the original Hartnup family,although in the latter study glutamine was apparentlymeasured as glutamic acid.

Indoles.-Baron et al. (1956) and Jepson (1956)reported an abnormally high excretion in membersof the Hartnup family of four indoles, namelytryptophan, indican, indolylacetic acid, and indolyl-acetylglutamine. This pattern has been reproducedin M. of family A on each occasion his urine hasbeen tested (by two-dimensional paper chromato-graphy) over a period of six years. J. and E. infamily B have been examined on nine occasionsover three years with a rather different result: thus,although the level of indican was consistently raisedin all specimens, tryptophan was generally onlymoderately raised, whilst indolylacetic acid andindolylacetylglutamine were within normal limitsin all specimens.

Several specimens from all three cases containedan unknown indole not described by Baron et al.(1956) or by Jepson (1956) in the Hartnup familycases. On two-dimensional chromatograms thisoccupies a position roughly between the origin andthe urea spot (Rodnight and Aves, 1958); the purpleappears very rapidly after the application of Ehrlich'sreagent and fades to invisibility within three minutes.Its nature has not yet been investigated.

Quantitative estimates of the daily output of someurinary indoles, including those mentioned above,are quoted in Table III for Case M. of family A andfor the three siblings of family B. Indican excretion

TABLE IIIDAILY URINARY EXCRETION OF INDOLES

~Family A Family BIndoleM. J. E. B.

Tryptophan (mg./24 hr.) - 40 40 15Indican (mg./24 hr.) 196 350 390 106Indolylacetic acid (mg./24 hr.) 5-0 1-70 0 95 8-30

Indolylacetylglutamine(approximate estimatemg./24 hr.) - 1 0 50 1

5-Hydroxyindolylaceticacid (mg./24 hr.) 1-50 1-70 1-65 3-25

Serotonin (,ug./24 hr.) 30 42 33 55Tryptamine (,ug./24 hr.) 65 67 19 50Unknown fast reactorbelow urea Present Present Present Absent

is markedly raised in Cases J. and E., high butalmost within normal range in Case M., and normalin theunaffected subject B. Confirming the impressiongained from the qualitative chromatography, theoutputs of indolylacetic acid and indolylacetyl-glutamine are normal in all the affected cases; therather high value for indolylacetic acid obtainedfrom the normal sister B. was also noted in two otherspecimens from this subject.The other urinary indoles measured were

serotonin, its principal metabolite in the body(5-hydroxyindolylacetic acid) and tryptamine; thelatter is a possible precursor of indolylacetic acid.The output of serotonin tended to be low in theaffected cases, but the values lie just within thenormal limits of 30 to 120 /Ag. i 20% per day asestablished at present (Rodnight, 1956, 1959b). Arather lower output of only 20 ,Xg./day was obtainedon another 24-hour sample from Case E. Withregard to the excretion of 5-hydroxyindolylaceticacid, the values quoted in Table III for the affectedcases are all below the lower limit of the normalrange, but that for the normal subject B. may beconsidered as normal. Tryptamine output wasnormal in all the subjects.Whole blood indoles were examined on one

occasion in the two affected members of family B.No qualitative differences were detected from thepattern previously established in normal subjects(Rodnight, 1959b).

Urinary Kynurenic Acid and Xanthurenic Acid.-These metabolites were determined as they lie on thepathway from tryptophan to nicotinamide. Theresults of estimates made on the 24-hour samplesfrom family B. are quoted in Table IV together withthe 24-hour outputs of several normal subjects,since few normal values using the fluorometricmethod have been published as yet. The output ofkynurenic acid in the affected subjects is definitelylower than in the normal sister or in the othernormal subjects; a similar difference, though lessmarked, is also apparent in output of xanthurenicacid.

TABLE IVURINARY KYNURENIC AND XANTHURENIC ACIDS

Kynurenic XanthurenicSubjects Acid Acid

(mg./24 hr.) (mg.f/24 hr.)

Family BJ. 0-74 1-75E. 0-66 1-54B. 2-10 2-25

Normal subjectsMale, 23 yr. 2-28 2-15Male, 24 yr. 2-68 1-66Male, 26 yr. 3-85 3-25Female, 23 yr. 3-95 2-60Female, 24 yr. 3-80 5-10

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L. A. HERSOV AND R. RODNIGHT

DiscussionAll suspected cases of Hartnup disease at the

Maudsley Hospital over the past four years havebeen carefully screened for indicanuria and amino-aciduria, with negative results except for the newcases reported here. In an earlier study no case ofsevere indicanuria had been found amongst 50 un-selected new admissions to another mental hospital(Rodnight and Mcllwain, unpublished data) norwere any instances of the Hartnup indole patterndetected in a more recent study of indole excretionin 156 unselected mental hospital patients (Rodnightand Aves, 1958). Further cases of the condition re-ported by other authors since the original account ofBaron et al. (1956) comprise three children describedby Jonxis (1957) members of two different con-sanguineous families in Holland, a 4-year-old girlreported by Henderson (1958), and a 7-year-old girlreported by Weyers and Bickel (1958) fromGermany. Thus, so far as we are aware, the presentaccount brings the total number of publishedinstances of the condition up to 13 cases occurringin eight families, three of which are consanguineous.The condition therefore appears a very rare one,but we agree with Baron et al. (1956) in consideringthat some caution is still necessary before acceptingthis conclusion, particularly since the clinicalmanifestation of the disease has now been shown tobe quite variable and often relatively mild in charac-ter, so that minor attacks in subjects with thebiochemical defect may well go undetected or un-diagnosed. Moreover, it now appears that attacksof the disease may only occur very rarely, as ex-emplified by the present patients, all of whom havesuffered only one major attack, which in J. and E. offamily B was delayed until early adult life.

In the previous accounts of Hartnup disease citedabove, the psychiatric features of the clinical picturehave ranged from emotional lability in the mildercases to apathy, irritability, depression, confusion,and delirium in the more severe cases. In the earliercases, however, these symptoms were apparentlypreceded and overshadowed by neurological andother features, since in no case were they the primarycause of referral to hospital. In the attacks sufferedby our patients, psychiatric symptoms were aprominent clinical feature, taking the form ofhallucinations and delusions in the boy (Case M.,Hersov, 1955), depression and depersonalization inCase E., and an anxiety reaction in Case J. Inclassical pellagra, also, the presenting symptomsmay vary considerably, some subjects exhibitingpsychiatric disturbances to a greater extent thanothers (Bicknell and Prescott, 1953).The psychiatric symptoms occurring in Hartnup

disease appear to be non-specific reactions, which

respond well to treatment and leave no residualeffects. Hallucinations and delusions are well-known accompaniments of toxic and infectiousconditions in childhood (Kanner, 1948). De-personalization has been described by Mayer-Gross(1935) in organic cerebral disease and in normalsubjects in states of fatigue; he views it as a pre-formed functional response of the brain in the samecategory as other non-specific preformed functionalmechanisms such as epileptic fits, delirium, states ofsemi-consciousness, and catatonic states.The suggestion was made by Baron et al. (1956)

that the biochemical defect in Hartnup disease mayslowly cause progressive mental deterioration. Ourown data give no support to this suggestion. TheI.Q.s of our patients were all within the averagerange, and Case E. in fact showed a raised I.Q. whenretested eight years after her first attack (the scoresof the progressive matrices for 1949 and 1958 wereI.Q. 94 and I.Q. 107 respectively). Nor has anydecline in school progress or work record beenobserved in our patients over a long period of time.The conclusion of Baron et al. (1956) was basedmainly on their finding that the I.Q.s of the fouraffected children in their family diminished from avalue of 101 in the youngest to 61 in the eldest, andalso on the mother's report of an apparent deteriora-tion in behaviour as they grew older with theappearance of bullying attitudes and disagreeablemoods. Such behaviour is commonly seen inchildren and adolescents as a reaction to the handi-cap of illness, periods in hospital, and educationalbackwardness, and is in no way comparable withdeterioration as commonly defined: a progressivechange in the direction of decreasing efficiency in theperformance of certain tasks as compared with pastperformance. Similarly the decline in I.Q. with agemight also be ascribed with equal justification todetrimental environmental influences as to genuinedeterioration, since the I.Q.s in the affected childrenwere lowest in whom the attacks of the disease hadbeen most frequent and severe, and highest in caseswith mild symptoms or no symptoms. In our view,therefore, the psychological evidence of Baron et al.(1956) is inadequate to support the conclusion that aprogressive decline in intellect occurs in Hartnupdisease, particularly since it fails to take into accountthe effects of illness and repeated periods in hospitalon I.Q. scores and social skills.The biochemical observations on the present

cases mainly confirm the work of Baron et al. (1956)and Jepson (1956); in particular they emphasizethe remarkable uniformity of the defect in amino-acid excretion. With regard to the indoles, it is nowclear both from the present work and from that ofMilne, Crawford, Girao, and Loughridge (1959)

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that a raised excretion of indolylacetic acid andindolylacetylglutamine is not a constant charac-teristic of the disease. In our cases, however,indican excretion has always been high, and in theabsence of facilities for preparing amino-acidchromatograms determinations of indican may serveas a useful guide in suspected cases, although thefinal diagnosis must rest on the demonstration ofthe typical aminoaciduria. The excretion ofserotonin has not been previously investigated inHartnup disease, but it appeared possible that thisimportant pathway of tryptophan metabolism, aswell as the route to nicotinamide, might also beaffected by the distortion of tryptophan utilizationwhich occurs in the disorder. In fact no majorabnormality was found in the present study, but thedaily output of 5-hydroxyindolylacetic acid and to alesser extent that of serotonin itself, tended to belower than normal in the affected subjects.Although more results are necessary to confirm thistendency, the present figures suggest that somediversion of tryptophan from the pathway ofserotonin formation may occur in the disease. Sucha diversion would be consistent with the suggestionof Milne et al. (1959) that the distortion of trypto-phan metabolism may be due to a defect in thetransport of tryptophan rather than to a deficiencyof tryptophan peroxidase. However, in phenyl-ketonuria, another hereditary disease, an establishedenzyme deficiency is associated with a deficiency inserotonin (Pare, Sandler, and Stacey, 1957).Low excretion rates were also obtained for

kynurenic acid, a result which confirms the observa-tion of Milne et al. (1959) that Hartnup subjectsmetabolize an abnormally low percentage of ingestedtryptophan to kynurenine, the precursor of kynurenicacid.

SummaryThe clinical and biochemical features are described

of three cases of Hartnup disease presenting with

non-specific psychiatric disorders. No evidence formental retardation or deterioration was found in thepatients.

Generally normal values were found for the excre-tion of indolylacetic acid and indolylacetylglutamine,but in conformity with previous work the excretionrate of indican in the patients was consistentlyraised. Low excretion rates were found for sero-tonin, 5-hydroxyindolylacetic acid, and kynurenicacid.

We wish to express thanks to our colleagues for theirhelp in this study. In particular we are very grateful toProfessor H. Mcllwain for his encouragement and advicethroughout the work, to Dr. Denis Leigh for permissionto use his case records and for much helpful advice, andto Dr. C. Potts for cooperation in following up one ofthe subjects. Mr. E. K. Aves rendered excellent technicalassistance. The work was assisted by a grant from theResearch Fund of the Bethlem Royal and the MaudsleyHospital, which we acknowledge with thanks.

REFERENCESAsatoor, A., and Daigliesh. C. E. (1956). J. chemn. Soc., p. 2291.Baron, D. N., Dent, C. E., Harris, H., Hart, E. W., and Jepson, J. B.

(1956). Lancet, 2, 421.Bicknell, F., and Prescott, F. (1953). The Vitamnins in Medicine,

3rd ed., p. 354. Heinemann, London.Evered, D. F. (1956). Biochem. J., 62, 416.Henderson, W. (1958). Arch. Dis. Childh., 33, 114.Hersov, L. A. (1955). J. ment. Sci., 101, 878.Jepson, J. B. (1956). Biochem. J., 64, 14P.Jonxis, J. H. P. (1957). Ned. T. Geneesk., 101, 569.Kanner, L. (1948). Child Psychiatry, 2nd ed., p. 449. Thonias,

Springfield, Illinois.Mayer-Gross, W. (1935). Brit. J. med. Psychol., 15, 103.Milne. M. D., Crawford, M. A., Girao, C. B., and Loughridge, L.

(1959). Biochem. J., 72, 30.Pare. C. M. B., Sandler, M., and Stacey, R. S. (1957). Lancet, 1,

551.Rodnight, R. (1956). Biochem. J., 64, 621.

(1959a). Proceedings of Third International NeurochemicalCongress, Strasbourg.

- (1959b). Ph.D. Thesis. London University., and Aves, E. K. (1958). J. ment. Sci., 104, 1149.and Mc!lwain, H. (1955). Ibid., 101, 884.

Satoh, K., and Price, J. M. (1958). J. biol. Chem., 230, 781.Sharlit, H. (1933). Ibid., 99, 537.Smith, I. (1958). Chromatographic Techniques. Heinemann,

London.Weyers, H., and Bickel, H. (1958). Kli,i. Wschr., 36, 893.

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