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Br FREDERICK HUDSON, ?

a consultant paediatrician in Liverpool, disease which can cause subnormality . .

explains

a rare

ome children

now being educated in normal QOols in this country might have been in hospils for the mentally subnormal if they had been a few years earlier. They are children with ne of the rare metabolic diseases which cause ental deficiency but which will respond to treatwith a special diet. At present only about ^ f a dozen such diseases are known?most are v rare?and, although they provide an exciting eakthrough in prevention and treatment, the total rnber of individuals involved is but a small frac-

Q?rn

brry

n of the vast numbers of

mentally handicapped,

is probably the commonest of diseases and the one which has been most ' ^ ensively studied. It may occur in about one babies out of all those born in the United each year. was ^rst detected a I Httlle over thirty years ago. A Norwegian and his r e had two children, a boy and a girl, and both ere severely mentally retarded. The parents were d to find the cause of this tragedy and to ?rrn'ned children to see many doctors, but their estions remained unanswered?so often no cause r mental retardation can be found.

en^etonuria

th ?

jOdred

^gdom

^

qu?

Eventually

examined by Dr. intrigued by the olivecolour that developed when he added a

Jorn

***

the children

Foiling.

ut'on of ferric chloride

heCre

vvas

were

He became

something

new

to the

children's urine.

to his

experience,

and

determined to find the explanation. After forty litres of urine from these children hi$ was rewarded. He isolated a substa ^ers^stence known as phenylpyruvic acid, the cause of th nce. ?live green colour. (Phenylpyruvic acid is a hence the name Phenyl-ketone#| ^r* tolling then searched the mental insti'?ns in Norway and found other patients with an

Sin.g

p^e Urienylketone, Jtut*

the

same

severe

retardation and the same subpublished the result of

stance in the urine and he

his work. In the next few years the disease was studied in other countries, notably by Professor Lionel Penrose in England and Dr. George Jervis in America. The clinical picture that emerged was of a baby, normal at birth, apparently normal for the first three or four months of life, but thereafter show-

ing mental retardation of a steadily increasing severity, until, by the age of four, most could not walk, or talk, and the average I.Q. was around 40. Many P.K.U. patients have blond hair and blue eyes, but this is not invariable. Many have eczema in early infancy and at least a quarter of them have epileptic convulsions. As with most diseases, the severity varies from one patient to another and a few have the biochemical changes of the disease yet a normal (or near normal) intelligence, but

such fortunate ones are very few indeed. The reason for the presence of phenylpyruvic acid in the urine is a defect in the metabolism of phenylalanine. Phenylalanine is an aminoacid and is one of the constituents of all protein foods. It is broken down in the liver by an enzyme, phenylalanine hydroxylase, and this enzyme is absent or defective in the patient with P.K.U. Soon after the war a young German paediatrician named Horst Bickel (he is now professor of paediatrics in Heidelberg) came to England to work in the Department of Child Health in Birmingham. Along with other research workers, he devised a means of removing phenylalanine from protein and found that a diet containing only a fraction of the usual quantity of phenylalanine would correct the abnormal metabolic findings in the patient with P.K.U. Unfortunately, the treatment made little or no difference to the mentally retarded patient, but hope was raised that early

23

treatment might be effective and prevent retardation from developing. The next stage in the history of this fascinating disease concerns the research work designed to make early detection (of a disease affecting only about one baby in ten thousand) a practical proposition. 'Early detection' means in the first few weeks of life, before the infant shows any clinical abnormality. The first big step in this country was taken just over ten years ago when the Phenistix test was introduced. Most people are now familiar with this test which is usually done by a Health Visitor on the baby's wet napkin. This test has detected many cases early enough for effective treatment, but it is not a perfect test and an appreciable number of cases have been missed. If the diagnosis is missed in infancy it is seldom made in time for effective treatment. A test employing a sample of blood offers a better chance of success. In Buffalo, U.S.A., Dr. Robert Guthrie worked for many years as a 'back-room' bacteriologist studying the genetics of bacteria. He became aware of the problem of early diagnosis of P.K.U. and turned his academic knowledge to great practical use. He devised what is now known as 'the Guthrie bacterial inhibition test'. This test uses blood obtained by pricking the baby's heel and allowing a few drops to fall on to a special piece of absorbent paper. The laboratory technique for analysing the blood sample is simple and rapid, and one technician can process about 5,000 tests a week. The Guthrie test has now been recommended by the Ministry of Health, on the advice of the Medical Research Council, for use in England and Wales, in preference to the Phenistix test. It is already in use in most of Scotland and also in Eire. Other equally effective tests employing blood samples are available and in use on a small scale in some laboratories in England. The problem of early detection is not now one of laboratory technique but of the administrative organisation needed to ensure that all babies are tested. Does early treatment of P.K.U. really allow the child to develop normally? The answer depends on what is meant by normal development. No child who has started treatment really early and who has kept carefully to the special diet has developed the devastating subnormality usually to be seen when no treatment has been possible. The majority of children who started treatment before the age of three months and who are now old enough for formal intelligence testing have an I.Q. averaging around 85, but very few show hope of

developing superior intelligence. It may be that some damage is done in the short time that must elapse before the diagnosis can be 24

confirmed; it may be that the special (and ver

restricted)

diet in

ment, but severe

some

way

impairs

full

develop

I.Q. of 80 or 90 instead o subnormality is enough to justify the expen even

an

sive and difficult treatment. The nutrition an< of children reared on the low phenyla lanine diet is usually excellent.

physique

The basis of the special diet is the exclusion o normal protein food such as meat, fish, eggs an< flour, and the substitution of a specially prepare^ low-phenylalanine protein powder and whea1 starch. The protein powder has an unpleasant taste but young infants accept it readily and a chil who has been brought up to accept it will seldofl regard it as unpleasant unless such a suggestion is made by a thoughtless adult. This is an impof tant

practical point that

must

be emphasised

to

al

who care for these children. The diet requires vert careful control and it should never be administered by anyone without experience or without the kno\*' ledge of its potential dangers. The cost of treatment is high, but it is borne b! the National Health Service. No one yet knoW* how long treatment must be continued. A children, unable for various reasons to tolerat? the diet for more than five years, have resume* normal food without any sign of deterioration^ but they have many years of life ahead of then1 There are, however, some scientific reasons i?' hoping that treatment will only be needed durifl? the first few years of life while the brain is growifl; rapidly. Cautious optimism is the right attitud

fe^j

at

present.

is an inherited disease and bot P.K.U. child are carriers of the defe< tive gene. The carriers are normal in health afl intelligence and they do not excrete phenylketone in the urine. They can usually be identified by sophisticated biochemical test, but the result the test is not always clear cut and it is too expel sive and time-consuming to be employed for t& widespread detection of carriers. When two carrie' are married there is always a one in four chan^ that any pregnancy will produce a phenylketonuf1 child. Although much has been learned about P.K..L since Folling's brilliant discovery, many problem remain. These are being studied intensively several countries and will be discussed at an intej national symposium to be held in Heidelberg tb summer. Collaboration between chemists and foO manufacturers may one day make the diet easi' for parents to prepare and more interesting i{ the patients. Fifteen years ago there seemed to ' no hope of treatment for this disease. In anotb1 fifteen years much that is written here may well' out of date if new scientific knowledge leads easier diagnosis and treatment.

Phenylketonuria

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Photo:

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A mother in Doncaster, Yorks, devised this notice to pin to her son when shopping. It

'Guthrie' blood test being made shortly after birth in the maternity ward. Cinephoto

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stops well-meaning biscuits.

people offering

Photo:

sweets or

Syndication International

25

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