328
SCREENING FOR PHENYLKETONURIA SIR,-You describe (Jan. 18, p. 178) the very efficient
phenylketonuria register in Liverpool and you rightly emphasise the need for better centralisation of the screening programme in the United Kingdom, suggesting that one laboratory might serve the whole country. You further ask the question whether " screening is any less successful in Scotland with just one laboratory than in England with 34 ". I am not in a position to answer this question, but I would point out that screening is more than a laboratory procedure, it is a human exercise which demands good communication between the patient, the local health authority, the screening laboratory, and the unit that gives the full sophisticated and experienced clinical and biochemical back up for the confirmation of diagnosis and the supervision of treatment.1 This would be difficult to obtain in any unit which screens more than 75,000 babies a year, since this demands a close relationship with many local authorities-26 in our particular case-as well as accepting 10-12 new metabolic problems each year in addition to clarifying the position in many indeterminate cases in the screening programme. I have long felt that the United Kingdom could be served by 10 efficiently organised regional biochemical genetics laboratories which would have further responsibilities in addition to screening and which would be closely linked with a regional cytogenetics unit, and I would be very distressed if serious consideration were given to the creation of a single screening unit. Willink Biochemical Genetics
Laboratory, Royal Manchester Children’s Hospital, Pendlebury, near
Manchester M27 1HA.
G. M. KOMROWER.
" work of all aides " doing such testing needs to be under the constant supervision of experienced medical doctors. Does universal periodic developmental assessment find the handicaps earlier ? Not many years ago, even in a university city with a medical school, children with cerebral palsy arrived for treatment at an average age of 2t years. Recently, in an area where periodic developmental assessment by doctors of child health clinics has been done for several years, a survey showed that 90% of cerebral-palsied children had started treatment during their first year, the remaining 10% being children recently coming into the
area.
Does earlier recognition of visual handicap, hearing deficity, cerebral palsy, mental or social handicap, improve the ultimate outcome ? It is not easy to find unequivocal evidence that it does in all these cases, but it seems possible and likely that it will be found to be true. It seems better 6 months rather than 18 months of age, and the National Child Development Survey has shown that children who still had squints uncorrected when they
to treat a cataract at
got to school were at a disadvantage. There is also need for research on methods and efficiency of periodic developmental assessment. There is certainly a great desire among doctors, notably those formerly in local authority services for children, to do these assessments; they would gladly cooperate in such research. There is need too for research on whether earlier treatment gives better results. There is at present some research in progress on results of Bobath treatment of cerebral-palsied children started under the age of 1 year. Perhaps the D.H.S.S. will see these areas as areas in which it will, under the Rothschild scheme, actively promote research. 35 Bloomfield Terrace, London SW1.
RONALD MAC KEITH.
UNIVERSAL PERIODIC DEVELOPMENTAL ASSESSMENT
SIR,-Professor Holland (Dec. 21, p. 1494) discusses screening in infancy and childhood. He starts from the " at risk " concept and rightly refers to the dangers of a " risk register " based on unvalidated characteristics and assumptions of outcome. But he does not present clearly the case for universal periodic developmental assessment of children.
Developmental assessment differs from looking for specific disorders, such as dislocation of the hip, heartdisease, or hernias. In problems of developmental delay, the mother suspects, or the doctor finds, developmental delay in one or more of the four main fields of development - movement, vision, hearing and language, everyday and social skills. The child is then referred to a centre for assessment and care for confirmation of the delay, identification of the underlying disorder, and diagnosis of the cause of The assessment must be comprehensive because that. delay in a particular field can have various causes. Delay in walking can be due to visual, motor, learning, or social handicap or to combinations of these. The second reason for comprehensive assessment is that handicap is usually multiple. A person who is mentally handicapped can also have a major refractive error, recognition and treatment of which is likely to help him or her. Developmental assessment is not a method of yes-no screening; the doctor doing it observes the quality of the child’s approach and of his achievement. Parts can be carried out by aides-e.g., vision testing of children over the age of six-and for pre-school children who are not brought to see the doctor for periodic medical examination and developmental assessment, the health visitor can do some tests when she visits the home. But her work and the 1.
Komrower, G. M. Pediatrics, Springfield, 1974, 53, 182.
A VARIANT OF PHENYLKETONURIA
SiR,-We were interested by the letter from Dr Bartholome (Dec. 28, p. 1580) reporting a patient with phenylketonuria and normal phenylalanine-hydroxylase activity. We reported a similar case1 in which the activity of phenylalanine p-hydroxylase was normal. This was measured by a method described previously,2 on a specimen obtained by needle liver biopsy. In the same paper we also described a pair of siblings with an identical syndrome (progressive neurological disease, chemical phenylketonuria, and failure to respond to a low-phenylalanine diet, in spite of satisfactory control of phenylalanine levels), in whom enzyme activity was not measured. All 3 patients have since died of bronchopneumonia at the ages of 2, 6, and 7 years. The clinical picture presented by these 3 cases was quite unlike that seen in any of the other 250 patients with classical or atypical phenylketonuria seen at the Hospital for Sick Children, London, since 1949. It is likely that Dr Bartholome’s and our cases represent a previously undescribed variant of the disease, though it is possible that the case described by Crome3 falls into the same category. A more detailed report of our 3 cases is in preparation. We have postulated that the disorder is due to a defect in the metabolism of biopterin, the natural cofactor for phenylalanine hydroxylase. An abnormality of the enzyme dihydropteridine reductase,4 which plays a vital role in the cofactor system, is a likely possibility. In neural tissue this enzyme and biopterin are involved in the hydroxylation of tyrosine to dihydroxyphenylalanine (dopa) and of trypto1. 2.
Smith, I. Archs Dis. Childh. 1974, 49, 245. McClean, A., Marwick, M. J., Clayton, B. E. J. clin. Path. 1973, 26,
3. 4.
Crome,
678. L. J. Neurol. 1962, 25, 149. Kauffman, S. Advanc. Enzymol. 1971, 35, 245.
329
phan to 5-hydroxytryptophan.5 Thus a defect in biopterin metabolism, in addition to interfering with the hydroxylation of phenylalanine to tyrosine, would impair the synthesis of the neurotransmitters, dopamine, noradrenaline, adrenaline, and serotonin. The likely outcome of such a defect would be a severe neurological illness. A low-phenylalanine diet, which would not affect the block in the synthesis of transmitters, would not be expected to alter the clinical course. This hypothesis would explain the features of these cases.
Jacobsonsuggested that pterins may have a place in the of phenylketonuria, and there is a particularly strong case for a therapeutic trial of such compounds in Dr Bartholome’s patient. We were unable to obtain sufficient biopterin for a clinical trial. Subsequently we have learntthat the analogue 6,7-dimethylpterin is readily synthesised, and we would like to suggest a therapeutic trial with this compound. It is active in vitro, although less Dr Jacobson has recommended a so than biopterin.4 starting dose of 0-5-1-0 mg. per kg. but, by analogy with the treatment of other inherited disorders responsive to cofactor (e.g., the treatment of homocystinuria with pyridoxine), the dose may have to be increased greatly before one can assume unresponsiveness. treatment
Institute of Child Health, 30 Guilford Street, London WC1N 1EH, and Hospital for Sick Children, Great Ormond Street, London WC1N 3JH.
ISABEL SMITH BARBARA E. CLAYTON OTTO H. WOLFF.
THE CONSULTANTS’ CONTRACT
SIR,-It would be wise to realise that there is, in Scotland, substantial number of whole-time consultants who are happy in their work and, in particular, happy with their present " open-ended " contract. Those men and women are devoted to their job, to their profession, and to humanity. One cannot be devoted to a Service, but they find the National Health Service an excellent framework within which they can exercise their many skills, and a vehicle by which skilled care can be brought to patients who need it. The present contract allows them to perform the multitude of duties normal to their job in as many and diverse hours as the situation calls for. In their routine working week, formal lectures, seminars, and clinical teaching of their own juniors, of undergraduate students, of general practitioners, of nurses, of theatre technicians, of health visitors, and of many others, has a real place. Clinical research, essential to the viability and vitality of all health care and certainly to the continued existence of the National Health Service has a role of varying importance. To this are added, of course, routine clinics, central and peripheral operating-lists, ward rounds, administration, interdepartmental liaison, and medical audit. There are also, of course, routine ward rounds at weekends and emergency (and sometimes routine) work in the evenings and during the nights and at weekends. Those consultants wish to be responsible for their patients. The consultant is responsible also for postgraduate and undergraduate assessment at local or national level and may have national or international commitments as an adviser or teacher. This is a broad outline of the routine duties of many whole-time consultants, the extent and variety varying a
&mid ot;
5. Blakely, R. L. The Biochemistry of Folic Acid and Related Pteridins (edited by A. Neuberger and E. L. Tatum). Amsterdam, 1969. 6. Jacobson, W. in Some Recent Advances in Inborn Errors of Metabolism (edited by K. S. Holt and V. P. Coffey); p. 1. Symposium 4. Society for the Study of Inborn Errors of Metabolism, Edinburgh, 1968. 7.
Jacobson, W. Personal communication.
from individual to individual. Those duties cannot be measured in hours, and certainly 40 hours is nothing like a routine working week. Certainly adequate remuneration for such effort is difficult to provide or calculate, and responsible expenses allowance is needed, but there is little wrong with the present system that could not be relatively easily corrected without interference with the principles of the contract or its associated provision. Those consultants would not wish to change the present openended contract which guarantees them freedom and opportunity to express themselves. Department of Obstetrics and Gynæcology, Ninewells Hospital, Dundee.
JAMES WALKER.
SIR,-As Mr Jones
says (Jan. 25, p. 218), many consulhave had doubts about the 10-session contract-forall since it was first mooted. They appreciate how much freedom an open-ended contract gives in the organisation of their multifarious and onerous duties, and they are beginning to understand how much a closed contract, with the supervision of their work this would bring, would circumscribe this freedom. There are many freedoms in medicine besides that to practice privately, and some of them tants
are
tremendously important.
But there is a problem. There are parts of the country with too few consultants and insufficient supporting staff, so that many consultants have too much work to do. To pay all consultants more, or to construct contracts based on itemised payment, will not solve the difficulties colleagues are having with their workload. This problem should not be insoluble given a constructive joint approach by the profession and the Department. The suggestion of service supplements in the " Castle " contract to achieve a more balanced distribution of consultants was a step in the right direction, although it did not go far enough. It would encourage those consultants who are hard-pressed to have this problem discussed in terms other than those of global pay and private practice. West Middlesex
Hospital,
Isleworth, Middlesex TW7 6AF.
N. F. COGHILL.
SiR,—Ibelieve the taking of sanctions by consultants of showing disapproval of the new contract offered by the Government to be wrong. I appreciate that the majority of my colleagues feel differently, but some, like myself, believe that any form of withdrawal of service will gain little in the short term and will result in harm to the profession in the long term. Any form of withdrawal of service from patients is a as a means
serious step which I am sure the present circumstances do not warrant. If we feel that the Government is forcing us into a situation where the service we give to the patients will deteriorate, then we must certainly say so. This means wide publicity of the new contract as it has been presented to us, with our arguments against it. We must make every effort to win sympathy and support from the public-only in this way can we honourably force the Government to make the changes we feel desirable. We must fight with our patients and not against them. Our present action can only antagonise the public, and we will fast lose their support and the respect in which we are now held, respect which has been won for us by our predecessors over many centuries. I ask the profession to stop the present action which I believe will achieve little of what we are asking and cause great harm to our good name. Our prime function is the
SCREENING FOR PHENYLKETONURIA SIR,-You describe (Jan. 18, p. 178) the very efficient
phenylketonuria register in Liverpool and you rightly emphasise the need for better centralisation of the screening programme in the United Kingdom, suggesting that one laboratory might serve the whole country. You further ask the question whether " screening is any less successful in Scotland with just one laboratory than in England with 34 ". I am not in a position to answer this question, but I would point out that screening is more than a laboratory procedure, it is a human exercise which demands good communication between the patient, the local health authority, the screening laboratory, and the unit that gives the full sophisticated and experienced clinical and biochemical back up for the confirmation of diagnosis and the supervision of treatment.1 This would be difficult to obtain in any unit which screens more than 75,000 babies a year, since this demands a close relationship with many local authorities-26 in our particular case-as well as accepting 10-12 new metabolic problems each year in addition to clarifying the position in many indeterminate cases in the screening programme. I have long felt that the United Kingdom could be served by 10 efficiently organised regional biochemical genetics laboratories which would have further responsibilities in addition to screening and which would be closely linked with a regional cytogenetics unit, and I would be very distressed if serious consideration were given to the creation of a single screening unit. Willink Biochemical Genetics
Laboratory, Royal Manchester Children’s Hospital, Pendlebury, near
Manchester M27 1HA.
G. M. KOMROWER.
" work of all aides " doing such testing needs to be under the constant supervision of experienced medical doctors. Does universal periodic developmental assessment find the handicaps earlier ? Not many years ago, even in a university city with a medical school, children with cerebral palsy arrived for treatment at an average age of 2t years. Recently, in an area where periodic developmental assessment by doctors of child health clinics has been done for several years, a survey showed that 90% of cerebral-palsied children had started treatment during their first year, the remaining 10% being children recently coming into the
area.
Does earlier recognition of visual handicap, hearing deficity, cerebral palsy, mental or social handicap, improve the ultimate outcome ? It is not easy to find unequivocal evidence that it does in all these cases, but it seems possible and likely that it will be found to be true. It seems better 6 months rather than 18 months of age, and the National Child Development Survey has shown that children who still had squints uncorrected when they
to treat a cataract at
got to school were at a disadvantage. There is also need for research on methods and efficiency of periodic developmental assessment. There is certainly a great desire among doctors, notably those formerly in local authority services for children, to do these assessments; they would gladly cooperate in such research. There is need too for research on whether earlier treatment gives better results. There is at present some research in progress on results of Bobath treatment of cerebral-palsied children started under the age of 1 year. Perhaps the D.H.S.S. will see these areas as areas in which it will, under the Rothschild scheme, actively promote research. 35 Bloomfield Terrace, London SW1.
RONALD MAC KEITH.
UNIVERSAL PERIODIC DEVELOPMENTAL ASSESSMENT
SIR,-Professor Holland (Dec. 21, p. 1494) discusses screening in infancy and childhood. He starts from the " at risk " concept and rightly refers to the dangers of a " risk register " based on unvalidated characteristics and assumptions of outcome. But he does not present clearly the case for universal periodic developmental assessment of children.
Developmental assessment differs from looking for specific disorders, such as dislocation of the hip, heartdisease, or hernias. In problems of developmental delay, the mother suspects, or the doctor finds, developmental delay in one or more of the four main fields of development - movement, vision, hearing and language, everyday and social skills. The child is then referred to a centre for assessment and care for confirmation of the delay, identification of the underlying disorder, and diagnosis of the cause of The assessment must be comprehensive because that. delay in a particular field can have various causes. Delay in walking can be due to visual, motor, learning, or social handicap or to combinations of these. The second reason for comprehensive assessment is that handicap is usually multiple. A person who is mentally handicapped can also have a major refractive error, recognition and treatment of which is likely to help him or her. Developmental assessment is not a method of yes-no screening; the doctor doing it observes the quality of the child’s approach and of his achievement. Parts can be carried out by aides-e.g., vision testing of children over the age of six-and for pre-school children who are not brought to see the doctor for periodic medical examination and developmental assessment, the health visitor can do some tests when she visits the home. But her work and the 1.
Komrower, G. M. Pediatrics, Springfield, 1974, 53, 182.
A VARIANT OF PHENYLKETONURIA
SiR,-We were interested by the letter from Dr Bartholome (Dec. 28, p. 1580) reporting a patient with phenylketonuria and normal phenylalanine-hydroxylase activity. We reported a similar case1 in which the activity of phenylalanine p-hydroxylase was normal. This was measured by a method described previously,2 on a specimen obtained by needle liver biopsy. In the same paper we also described a pair of siblings with an identical syndrome (progressive neurological disease, chemical phenylketonuria, and failure to respond to a low-phenylalanine diet, in spite of satisfactory control of phenylalanine levels), in whom enzyme activity was not measured. All 3 patients have since died of bronchopneumonia at the ages of 2, 6, and 7 years. The clinical picture presented by these 3 cases was quite unlike that seen in any of the other 250 patients with classical or atypical phenylketonuria seen at the Hospital for Sick Children, London, since 1949. It is likely that Dr Bartholome’s and our cases represent a previously undescribed variant of the disease, though it is possible that the case described by Crome3 falls into the same category. A more detailed report of our 3 cases is in preparation. We have postulated that the disorder is due to a defect in the metabolism of biopterin, the natural cofactor for phenylalanine hydroxylase. An abnormality of the enzyme dihydropteridine reductase,4 which plays a vital role in the cofactor system, is a likely possibility. In neural tissue this enzyme and biopterin are involved in the hydroxylation of tyrosine to dihydroxyphenylalanine (dopa) and of trypto1. 2.
Smith, I. Archs Dis. Childh. 1974, 49, 245. McClean, A., Marwick, M. J., Clayton, B. E. J. clin. Path. 1973, 26,
3. 4.
Crome,
678. L. J. Neurol. 1962, 25, 149. Kauffman, S. Advanc. Enzymol. 1971, 35, 245.
329
phan to 5-hydroxytryptophan.5 Thus a defect in biopterin metabolism, in addition to interfering with the hydroxylation of phenylalanine to tyrosine, would impair the synthesis of the neurotransmitters, dopamine, noradrenaline, adrenaline, and serotonin. The likely outcome of such a defect would be a severe neurological illness. A low-phenylalanine diet, which would not affect the block in the synthesis of transmitters, would not be expected to alter the clinical course. This hypothesis would explain the features of these cases.
Jacobsonsuggested that pterins may have a place in the of phenylketonuria, and there is a particularly strong case for a therapeutic trial of such compounds in Dr Bartholome’s patient. We were unable to obtain sufficient biopterin for a clinical trial. Subsequently we have learntthat the analogue 6,7-dimethylpterin is readily synthesised, and we would like to suggest a therapeutic trial with this compound. It is active in vitro, although less Dr Jacobson has recommended a so than biopterin.4 starting dose of 0-5-1-0 mg. per kg. but, by analogy with the treatment of other inherited disorders responsive to cofactor (e.g., the treatment of homocystinuria with pyridoxine), the dose may have to be increased greatly before one can assume unresponsiveness. treatment
Institute of Child Health, 30 Guilford Street, London WC1N 1EH, and Hospital for Sick Children, Great Ormond Street, London WC1N 3JH.
ISABEL SMITH BARBARA E. CLAYTON OTTO H. WOLFF.
THE CONSULTANTS’ CONTRACT
SIR,-It would be wise to realise that there is, in Scotland, substantial number of whole-time consultants who are happy in their work and, in particular, happy with their present " open-ended " contract. Those men and women are devoted to their job, to their profession, and to humanity. One cannot be devoted to a Service, but they find the National Health Service an excellent framework within which they can exercise their many skills, and a vehicle by which skilled care can be brought to patients who need it. The present contract allows them to perform the multitude of duties normal to their job in as many and diverse hours as the situation calls for. In their routine working week, formal lectures, seminars, and clinical teaching of their own juniors, of undergraduate students, of general practitioners, of nurses, of theatre technicians, of health visitors, and of many others, has a real place. Clinical research, essential to the viability and vitality of all health care and certainly to the continued existence of the National Health Service has a role of varying importance. To this are added, of course, routine clinics, central and peripheral operating-lists, ward rounds, administration, interdepartmental liaison, and medical audit. There are also, of course, routine ward rounds at weekends and emergency (and sometimes routine) work in the evenings and during the nights and at weekends. Those consultants wish to be responsible for their patients. The consultant is responsible also for postgraduate and undergraduate assessment at local or national level and may have national or international commitments as an adviser or teacher. This is a broad outline of the routine duties of many whole-time consultants, the extent and variety varying a
&mid ot;
5. Blakely, R. L. The Biochemistry of Folic Acid and Related Pteridins (edited by A. Neuberger and E. L. Tatum). Amsterdam, 1969. 6. Jacobson, W. in Some Recent Advances in Inborn Errors of Metabolism (edited by K. S. Holt and V. P. Coffey); p. 1. Symposium 4. Society for the Study of Inborn Errors of Metabolism, Edinburgh, 1968. 7.
Jacobson, W. Personal communication.
from individual to individual. Those duties cannot be measured in hours, and certainly 40 hours is nothing like a routine working week. Certainly adequate remuneration for such effort is difficult to provide or calculate, and responsible expenses allowance is needed, but there is little wrong with the present system that could not be relatively easily corrected without interference with the principles of the contract or its associated provision. Those consultants would not wish to change the present openended contract which guarantees them freedom and opportunity to express themselves. Department of Obstetrics and Gynæcology, Ninewells Hospital, Dundee.
JAMES WALKER.
SIR,-As Mr Jones
says (Jan. 25, p. 218), many consulhave had doubts about the 10-session contract-forall since it was first mooted. They appreciate how much freedom an open-ended contract gives in the organisation of their multifarious and onerous duties, and they are beginning to understand how much a closed contract, with the supervision of their work this would bring, would circumscribe this freedom. There are many freedoms in medicine besides that to practice privately, and some of them tants
are
tremendously important.
But there is a problem. There are parts of the country with too few consultants and insufficient supporting staff, so that many consultants have too much work to do. To pay all consultants more, or to construct contracts based on itemised payment, will not solve the difficulties colleagues are having with their workload. This problem should not be insoluble given a constructive joint approach by the profession and the Department. The suggestion of service supplements in the " Castle " contract to achieve a more balanced distribution of consultants was a step in the right direction, although it did not go far enough. It would encourage those consultants who are hard-pressed to have this problem discussed in terms other than those of global pay and private practice. West Middlesex
Hospital,
Isleworth, Middlesex TW7 6AF.
N. F. COGHILL.
SiR,—Ibelieve the taking of sanctions by consultants of showing disapproval of the new contract offered by the Government to be wrong. I appreciate that the majority of my colleagues feel differently, but some, like myself, believe that any form of withdrawal of service will gain little in the short term and will result in harm to the profession in the long term. Any form of withdrawal of service from patients is a as a means
serious step which I am sure the present circumstances do not warrant. If we feel that the Government is forcing us into a situation where the service we give to the patients will deteriorate, then we must certainly say so. This means wide publicity of the new contract as it has been presented to us, with our arguments against it. We must make every effort to win sympathy and support from the public-only in this way can we honourably force the Government to make the changes we feel desirable. We must fight with our patients and not against them. Our present action can only antagonise the public, and we will fast lose their support and the respect in which we are now held, respect which has been won for us by our predecessors over many centuries. I ask the profession to stop the present action which I believe will achieve little of what we are asking and cause great harm to our good name. Our prime function is the
