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AMINE-OXIDASE INHIBITORS AS POSSIBLE

TREATMENT FOR PHENYLKETONURIA

BRIAN H. KIRMAN.

C. M. B. PARE.

Fountain Hospital,London, S.W.17.

St. Bartholomew’s Hospital,London, E.C.1.

SIR,-Pare et all suggested that the mental defect inphenylketonuria may be partly caused by decreasedconcentrations of 5-hydroxytryptamine (5-H.T.) and

perhaps other monoamines in the brain. If so, then anymethod of increasing its concentration in the brain mightprove rational therapy. Some years ago we tried to dothis by treating affected children with iproniazid, whichinhibits monoamine oxidase, the enzyme responsible formuch of the further metabolism of biologically activemonoamines.4 This treatment would thus tend to raise theconcentrations of 5-H.T. and of catecholamines in thetissues.

Eight phenylketonuric children aged 7-15 years were

matched in pairs for sex, age, weight, and i.Q., and divided into

TABLE I-SERUM-5-HYDROXYTRYPTAMINE (mg. per ml.) BEFORE ANDDURING TREATMENT WITH IPRONIAZID (4 CASES) OR PLACEBO

(4 CASES)

two groups. One group was given iproniazid by mouth (50 mg.per day for 6 months); the other, an equal amount of placebo.Those responsible for evaluation of treatment were unawarewhich patients received the active drug.

Samples of blood and early-morning urine were collectedbefore and at intervals after treatment began for estimationof 5-H.T. and urinary 5-hydroxyindoleacetic acid (5-H.I.A.A.)(see Pare et al.1). Regular estimations of glutamic-oxaloacetictransaminase were carried out.There was no evidence during the trial that iproniazid

benefited these children, as judged by behaviour, electro-

encephalogram, or intelligence testing. No adverse effects ofthe drug were noted.Changes in the serum 5-H.T. and urinary 5-H.I.A.A. are

shown in tables i and II. Although the results vary consider-ably, there is an overall increase in serum 5-H.T. duringtreatment with iproniazid, and a less definite fall in urinary5-H.I.A.A.

Although only indirect evidence, these findings suggestthat iproniazid may be raising the brain concentration of5-H.T., as it does, together with catecholamines, in theexperimental animal. 5 The fact that iproniazid did notbenefit these phenylketonuric children is, perhaps, notsurprising in view of their ages. Woolf et al. state thattreatment is unlikely to benefit children over 2 years ofage, and then only if their i.Q. is more than 40. Irreversiblebrain damage does occur and it is likely that this beginsearly in life.’ 7 Now that safer monoamine-oxidaseinhibitors are available, we feel that a trial of such a drugwould be worth undertaking in young infants in whomirreversible brain damage is unlikely. This could ethically1. Pare, C. M. B., Sandier, M., Stacey, R. S. Lancet, 1957, i, 551.2. Pare, C. M. B., Sandier, M., Stacey, R. S. ibid. 1958, ii, 1099.3. Pare, C. M. B., Sandier, M., Stacey, R. S. Arch. Dis. Childh. 1959, 34, 422.4. Blaschko, H. Pharmacol. Rev. 1952, 4, 415.5. Spector, S., Prockop, D., Shore, P. A., Brodie, B. B. Science, 1958,

127, 704.6. Woolf, L. I., Griffiths, R., Moncrieff, A., Coates, S., Dillistone, F.

Arch. Dis. Childh. 1958, 33, 31.7. Crome, L., Pare, C. M. B. J. ment. Sci. 1960, 106, 444.

TABLE II—URINARY 5—HYDROXYINDOLEACETIC ACID (mg. per g.CREATININE) BEFORE AND DURING TREATMENT WITH EITHER

IPRONIAZID (4 CASES) or PLACEBO (4 CASES)

be undertaken when, for some reason, a phenylalanine-restricted diet is impracticable.We acknowledge the help of Prof. R. S. Stacey for estimations of

serum-5-H.T. and of Dr. M. Sandler for those of the urinary 5-H.I.A.A.and serum-transaminase.

1. Wheeler, P., Peterson, D. W., Michaels, G. D. J. Nutr. 1959, 69, 253.2. Evans, R. J., Bandemer, S. L., Davidson, J. A. Poult. Sci. 1960, 39, 1199.3. Sinclair, H. M. Lancet, 1956, i, 381.

ESSENTIAL-FATTY-ACID CONTENTOF HENS’ EGGS

SIR,-Changes in hens’ diets are known to affect thecomposition of the egg lipids.l2 2 Dr. Hugh Sinclair

implied, during a recent television interview, that methodsof poultry husbandry may also have a bearing on thedietary value of eggs. He preferred eggs from free-range orfarmyard hens to those from battery hens in a human dietwhich he believed would lower the incidence of athero-sclerosis in middle-aged men. This implies that free-range eggs contain more of the essential fatty acids (E.F.A.)which Sinclair has claimed are of value in preventingatherosclerosis.3We are at present using gas-liquid chromatography to

analyse the lipids of eggs from hens of similar breed housedunder different conditions and receiving diets appropriateto the environment. We are determining the E.F.A. in theegg lipids and recording their values during the entirelaying life of the birds.A brief assessment of our results to date may be of

interest because we have included both battery and free-range eggs in the study.On average over two months, the lipids from free-range eggs

contain 16-1% of E.F.A. and those from battery eggs 15’3%.This difference is unlikely to be of human dietary significancebecause the variation within each group was of the order1-2%.There are indications that seasonal variations in E.F.A.

contents are much greater than the differences between the two

groups at any one time. Eggs produced under these two methodsof husbandry are found to have closely similar E.F.A. contents,provided that they are sampled at the same time during thelaying period.

Other workers have found a relationship between the E.F.A.content of eggs and of the diet of the hen.1 In our experimentthe diet of’the free-range birds contained 1-52% of E.F.A. andthat of the battery birds 1’24%. From our results so far there isan implication that the E.F.A. are slightly more effectively trans-ferred to the egg in the case of the battery birds. We requiremore data before examining this point statistically.

In another experiment we supplemented the diet of batteryhens with 4% arachis oil. The feed contained 2-5% E.F.A.

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Eggs from these birds had an average E.F.A. content of 18’8%over a period of five months.

At this stage in our work there is no evidence to supportthe claim that eggs from free-range birds are likely to haveany real advantage over battery eggs as a source ofessential fatty acids in the human diet.The essential-fatty-acid content of eggs can be aug-

mented somewhat, as indicated above, by increasing theE.F.A. content of the hen’s diet, but whether this is necessarycan be determined only in the context of human require-ments, which seem difficult to evaluate in view of the

complexity of existing dietary patterns.J. B. M. COPPOCKN. W. R. DANIELS.

W. P. BLOUNT.

SYD FOX.

Spillers Ltd.,Technological Research Station,

Cambridge.B.O.C.M. Ltd.,

Stoke Mandeville.

The University, Reading.

Public Health

Diphtheria in CamberwellTHE outbreaks of diphtheria in London and other parts of

the country are disturbing. Between 1943 and 1957 the numberof notifications in England and Wales fell each year, butin 1958 there was a sharp increase and there were 8 diphtheriadeaths.

Camberwell, in south-east London, was free from diphtheriafrom 1948 to 1959, but from November of that year until earlyin February, 1960, 6 cases were reported, all in non-immunisedchildren, and 70 others were found to be harbouring the

organism. The outbreak was confined to one corner of the

borough and was linked with a primary school.There were no further cases until Dec. 19, 1960, when a

child aged 7 years, living in another part of the borough1 miles away, and attending a different primary school, wasnotified. The child had been ill for five days and went toschool on the second day of her illness before being sent to achildren’s hospital. The school closed for the Christmas

holidays on Dec. 21. Since then 29 children, most of themaged 6-7 years, who were either pupils at the same school orfamily contacts, have been sent to hospital-10 as clinical

cases, the remainder for isolation and investigation followingroutine swabbing of class and home contacts. So far, no casesor carriers have come to light in people living outside the areanear the school.

The present outbreak and the earlier one do not seem to beconnected. Corynebacterium diphtherice rjutis was the causativeorganism in both, but the recent cases tend to be more severe,many of them having the classical signs and symptoms,fortunately seldom seen today. A child of 7, a class contactof the first patient, has died.While many of the carriers had received primary immunisa-

tion, in only 1 of the clinical cases was there any record of this,but a reinforcing injection had not been given. It is estimatedthat over 70% of children in this part of London have beenimmunised in infancy, but the proportion protected by a" boosting dose " at school age must be very much less. It is

significant that nearly all the children affected in both outbreakswere of primary-school age.

Investigation and swabbing of the class contacts was

complicated by the school holiday, but it was nevertheless

accomplished quickly. As a result, active and passive immunisa-tion was begun early. Some hundreds of children were broughtto the special immunisation clinics opened on the school

premises, and attendances at other clinics in the borough haveshown a gratifying increase. The publicity given in the localand national press and on radio and television has, no doubt,also stimulated the public to cooperate.

Outbreaks such as this are a powerful reminder that failureto maintain a high rate of immunisation and reimmunisationmay have disastrous consequences.

Respiratory InfectionsDeaths attributed to influenza in England and Wales in the

week ending Dec. 31, 1960, numbered 45; this was almostdouble the figure for the previous week (23) and for the corres.ponding week in 1959 (24). 40 of these deaths were of patientsover 35, and 19 of patients over 74. Only 1 influenza death wasreported from the administrative county of London.

Deaths from pneumonia in the same week totalled 910, asagainst 792 the previous week, and 748 in the correspondingweek in 1959.

In the Midlands, many cases of respiratory-tract infectionhave been admitted to hospital, mostly with complications suchas pneumonia, haemorrhagic pneumonia, and cardiac involve-ment. Birmingham, Walsall, and parts of Worcestershire havebeen the worst affected within an area originally bounded byStoke and Stafford in the north, Wolverhampton in the west,Hereford and Worcester in the south, and Birmingham andWalsall in the east. The epidemic is now spreading to theeastern Midlands, and Derby, Nottingham, and Burton-on-Trent are affected. Claims for sickness benefit in Birminghamare three and a half times, and in Burton two and a half times,

. the normal level. The Birmingham bed bureau’s daily case-load of hospital admissions has been double that in the corres-ponding period in 1959.

Clear definition of the infection has been difficult because ofthe many cases of respiratory disease at this time of year. But

many patients had the clinical signs and symptoms of influenza;and in 19 of them in Birmingham serological evidence ofinfluenza-A infection was obtained. From 10 nurses and

patients (some of whom were included among the 19 above) avirus of variety A2 was isolated. Influenza virus A was alsoisolated from a fatal case.

Medical and nursing staffs have been depleted; in 4 hospitalsin Staffordshire, for example, 10"., of the 400 nurses haveinfluenza and this number is increasing at the rate of 10 to 15a day. Many hospitals have been forced to restrict surgery tourgent cases.

We are indebted to Dr. C. W. Gordon, senior administrativemedical officer, Birmingham Regional Hospital Board, for help incompiling this note.

Divided ResponsibilitiesIn his report for 1959 Dr. R. J. Dodds, medical officer of

health for Smethwick, comments on a growing tendency topass on responsibility within the National Health Service. This,he says, can be traced back to a feeling in the earlier years of theN.H.S. that services were overlapping and being duplicated:in the field of home care instances were cited of 15-20 differentvisitors calling on the same family. The natural outcome wasa proliferation of liaison and coordination committees, whichin turn gave rise to numerous standing and ad-hoc sub-committees. All of these have done excellent work, but at aconsiderable cost in time, energy, and patience of highlyskilled staff.The next phase began when someone realised that only by

contracting out of traditional obligations could the waiting-listsand vast building programmes be tailored to the limitednational resources. Only patients needing active nursing andmedical care were to be looked after in hospitals; other agencieswould care for the remainder. Dr. Dodds states that theefficiency of a geriatric service appears to be gauged by only oneindex: the number of discharges per bed-year-and the morethe merrier. Local welfare authorities, to whose care thesepatients are discharged, are not in general well equipped to dealwith large numbers; and the problem is aggravated by the long-overdue abandonment of workhouse accommodation in favourof small homes which may lack facilities and staff to deal withthe really infirm.