Early diagnosis is important in many inherited metabolic diseases, since prompt intervention can prevent complications. Neo-natal screening is one way to achieve this.

Screening for phenylketonuria (PKU) was introduced in the UK a little over 30 years ago. The incidence of this condition in the UK is approximately 1:10,000. Deficiency of phenylalanine hydroxylase leads to high blood levels of phenylalanine which are toxic to the developing brain: chronic exposure leads to microcephaly, mental handicap and epilepsy. Since phenylalanine is an essential amino acid, dietary restriction can lower levels and markedly improve the outcome. The necessary protein restriction is very severe and the diet is, therefore, very demanding. Moreover, patients must take supplements of vitamins and minerals and a protein substitute containing all amino acids except phenyl-alanine. Blood phenylalanine levels need to be monitored regularly and the diet modified accordingly. The difficulty of treatment must not be underestimated and outcomes are still less good than one might wish. Nevertheless, screening and treatment of PKU has been a success(1).

In the UK, within the next few years, neonatal screening will probably be introduced for medium chain acyl-CoA dehydrogenase (MCAD) deficiency. In north west Europe, this is the commonest defect of fatty acid oxidation, with an incidence of approximately 1:15,000 in the UK(2). In these patients, infection or fasting can lead to high blood levels of fatty acids and hypoglycemia: together, these bichemical changes lead to encephalopathy with a high risk of permanent neurological damage or suden death(3). In contrast to PKU, the treatment of MCAD deficiency is simple. Most of the time, patients can be treated like any other child but fasting must be avoided and a regular carbohydrate intake must be maintained during infections or other illnesses(4). Analysis of blood acyl-carnitines by tandem mass spectrometry now provides a highly sensitive and specific screening test for this condition(5). The capital cost of a tandem mass spectrometer is high but the cost for analysis of each sample is low and the technique can use the same blood spots that are already collected for neonatal screen-ing. Furthermore, transition to tandem mass spectrometry would also increase the efficiency of screening for PKU(6).

Why, then, has screening for MCAD deficiency not yet been introduced in the UK? When confronted with bereaved parents, metabolic pediatricians are sometimes tempted to blame it on the inertia of a National Health Service, but there are some better reasons. Most importantly, although we have considerable knowledge about MCAD deficiency, the natural history is still uncertain. Most cases of MCAD deficiency are homozygous for a single prevalent point mutation(7). Environmental stress seems to determine if and when patients develop symptoms(8). Following the diagnosis of a patient with MCAD deficiency, investigation of family members often reveals asympto-matic individuals with the biochemical defect(3). It is not yet known how many patients with MCAD deficiency remain asymptomatic throughout life. Obviously, if only a small proportion of patients develop symptoms, the cost:benefit ratio for screening would be less favorable than is generally assumed. It seems likely that at least 50% of patients with MCAD deficiency develop symptoms(2). Nevertheless, before introduc-ing screening, UK Health Authorities may insist on a large-scale long-term controlled study. One proposal is that blood spots from half the country should be analyzed for MCAD deficiency at birth and affected cases given appropriate counselling, whilst blood spots for the other half of the country are stored and analyzed for MCAD deficiency at the age of a few years. This would establish the natural history and also the effectiveness of treatment. Treatment of MCAD deficiency is known to be effective in patients presenting acutely(9) but it has been suggested that treatment might be implemented less well in patients diagnosed by neonatal screening.

What is the relevance of this to India? As mentioned earlier, the high incidence of MCAD deficiency in the UK results from a single mutation which originated in Eastern Europe and spread westwards(7). The incidence of MCAD deficiency in India is unknown but it is likely to be extremely low. There is greater molecular heterogeneity in PKU: again, the incidence in India is unknown but it is probably low(10). Neonatal screening for these conditions would, therefore, be much less cost-effective in India than in the UK.

Tandem mass spectrometry can detect a number of other metabolic disorders as well as MCAD deficiency and PKU. These include most fatty acid oxidation disorders, many organic acidemias, maple syrup urine disease, tyrosinemia and citrullinemia(11). Some cases of homocystinuria can be detected by means of high methionine levels but pyridoxine responsive cases would be missed. Given the large number of conditions that might be detected, is neonatal screening by tandem mass spectrometry justified within the private sector in India ? Screening for these disorders will probably not be introduced in the UK (though it has been proposed if tandem mass spectrometry is used to detect MCAD deficiency). This is partly due to the rarity of the disorders but largely because treatment is less effective than for MCAD deficiency and PKU. The disorders are more heterogeneous than MCAD deficiency, their natural history is less well established and more work is needed on the sensitivity and specificity of detection using mass spectrometry. Finally, the symptom-free interval for many of these disorders is very short. Screening for galactosemia was abandoned in the UK because patients presented clinically before screening results were available(12). For many patients with long-chain fatty acid oxidation disorders, organic acidemias and citrullinemia, the symptom-free interval is less than 3 days – much less than for galactosemia. Clearly, these conditions fulfuil few of the Wilson and Jungner criteria for screening(13). In India, the evidence to support screening is no stronger than in the UK. There are hardly any data concerning the incidence of these metabolic diseases in India, their natural history or the effectiveness of treatment. Moreover, screen-ing is not without its problems. Besides costs these include: (a) the need to obtain informed consent without creating anxiety, and (b) parental expectations that, if screening is undertaken, all cases will be detected and effective treatment is available.

If neonatal screening is not introduced, how can the outcome be improved for inborn errors of metabolism? First, prompt investiga-tion should be undertaken in all patients developing relevant symptoms. Metabolic investigations should be undertaken parti-cularly readily in neonates. If a baby deteriorates after an initial period of health, at the same time as a septic screen, blood should be sent for measurement of glucose, pH, ammonia and, if available, analysis by tandem mass spectrometry(14). Similar investigations should be undertaken in older patients developing unexplained encephalopathy. If acylcarnitine analysis is available, other indications include unexplained hypogly-cemia, cardiomyopathy, rhabdomyolysis or maternal acute fatty liver of pregnancy(15). A second step towards improving the manage-ment of metabolic diseases in India would be to undertake research to establish the inci-dence of these conditions, the spectrum of severity and the effectiveness of current treatment.

In summary, having the technology to undertake neonatal screening for a range of metabolic diseases does not mean this is the right thing to do. To answer this question, one needs local information about incidence, natural history and effectiveness of treatment.

Andrew A.M. Morris,
Senior Lecturer in
Pediatric Metabolic Medicine,
University of Newcastle upon Tyne, UK.
E-mail: [email protected]