New developments in neonatal screening.

There have been significant advances in the methods available for the detection and investigation of individuals with inherited metabolic disorders. The burgeoning of molecular biology in recent years and the discovery of new classes of inherited metabolic disorders, such as inborn errors of fat oxidation, are well known. What is perhaps less well recognised, is that there have been comparable advances in analysis and laboratory automation. The combination of the development of generic analytical technology of great power and sophistication, and the discovery of new treatable metabolic diseases detectable in the newborn period, has, we believe, resulted in a sea change in neonatal screening. Neonatal screening for metabolic diseases became feasible as a result of the pioneering work of Guthrie. He developed a simple, robust, and eVective technique for the detection of elevated concentrations of phenylalanine in blood—the “Guthrie Test”— which was used to detect phenylketonuria by means of a semi-quantitative microbiological bioassay. Screening for this disorder (PKU; phenylalanine hydroxylase deficiency; McKusick 261600) was subsequently implemented in the UK in 1969. The specimens used are dried blood spots which are usually collected by means of a heel-prick on the sixth day of life, although later sampling, up to 14 days, can occur. This form of specimen collection has become almost universal. Quantitative assays specific for phenylalanine have been introduced by some centres, driven by the desire to introduce a degree of automation. 4 An alternative approach is to use chromatographic methods, and this has been adopted by some centres. The proponents of this technology contend that other inherited disorders of amino acid metabolism can be detected and that improved prognosis may be achieved by early diagnosis. However, chromatographic methods are time consuming and diYcult to automate, particularly in respect of the recognition of abnormal chromatograms. None the less, the concept of a generic technology capable of detecting several disorders by a single procedure is attractive, and single dimension paper and thin layer chromatography with ninhydrin staining has been used successfully for many years in some centres in the UK for the detection of PKU and other inherited disorders of amino acid metabolism. The justification for PKU screening is that early detection of aVected individuals and the introduction of treatment, a diet low in phenylalanine, avoids irreversible brain damage. 7 Similarly, the measurement of TSH or thyroxine for the detection of congenital hypothyroidism was adopted throughout the UK in 1981 and is also universal. The dried blood spot, it turns out, is a surprisingly robust form of sample collection and a plethora of conditions have been proposed as candidates for neonatal screening, although the benefits are sometimes far from clear. The ability to detect genetic disease directly by means of molecular biological techniques suggests that, at least in principle, screening for all inherited conditions is possible.However, in most inborn errors a given phenotype is caused by a large number of diVerent mutations and thus if direct mutational analysis is contemplated a multiplicity of probes is required.Clearly, novel previously unknown mutations contributing to a given pathological phenotype would be missed. Since the introduction of the Guthrie test there has been a remarkable expansion in the known number and types of inherited metabolic disorders. Thus new classes of disorders such as inherited defects of mitochondrial â-oxidation, peroxisomal metabolism, and of the respiratory chain are now known. Furthermore, the early concept of an inborn error of metabolism presenting as a florid biochemical disorder detectable in the first days of life has been modified by the recognition of episodic, late presenting disease. The commonest of the â-oxidation disorders, medium chain acyl-CoA dehydrogenase deficiency (MCAD), presents most frequently with episodic hypoglycaemia which may be life threatening. These hypoglycaemic episodes can be precipitated by otherwise unremarkable intercurrent infections, or simply by prolonged fasting. Conventional investigations during periods of remission are generally uninformative, but characteristic abnormal acylcarnitines are detectable in blood. MCAD is readily treated by the simple dietary manipulation of the avoidance of fasting, although if a metabolic crisis secondary to stress should occur, more aggressive intervention such as the intravenous administration of glucose is necessary. ThusMCAD,which is at least as common as PKU, is easily and cheaply treated, and failure to recognise children with the disorder and institute timely and appropriate management can lead to brain damage or death.MCAD is one of several inborn errors of mitochondrial â-oxidation. Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and very long chain acyl-CoA dehydrogenase deficiency (VLCAD) are also members of this group of disorders and seem to be relatively common and amenable to dietary treatment. The question arises: is it possible to detect MCAD and other disorders of â-oxidation by analysis of dried blood spot specimens? Archives of Disease in Childhood 1997;77:F151–F154 F151