The Power of New Technologies to Extend the Scope of Screening.

Peter T Clayton MD FRCP FRCPCH, Professor of Paediatric Metabolic Disease and Hepatology, Institute of Child Health, UCL, and Great Ormond Street Hospital.

Over the past 5 years, there has been a dramatic increase in the number of disorders included in neonatal screening programmes in some parts of the world, notably in the USA, Germany and Australia. This development has been largely technology driven, and one major technique that has contributed has been the development of electrospray ionisation mass spectrometry (ESI-MS). This technique makes possible the ionisation of non-volatile analytes with masses ranging from that of the smallest aminoacid (glycine), and, in an instrument with a modified quadrupole, to a small virus or organelle (e.g. a ribosome). Specificity is enhanced dramatically by the use of a collision cell and a second quadropole (ESI-MS/MS). "Tandem" mass spectrometry is now routinely used for the detection of abnormal blood spot concentrations of amino acids and acyl carnitines. Other analytes that can be measured in a blood spot include bile acids, 17-hydroxyprogesterone, disialotransferrin and sickle haemoglobin. The list of metabolites that can be measured by ESI-MS/MS grows daily, and the potential for the use of some of these in blood spot screening will be discussed.

Another development in mass spectrometry, time of flight mass spectrometry (TOF-MS), e.g. matrix-assisted laser desorption ionisation mass spectrometry (MALDI-TOF-MS), has also made analysis of peptides and small proteins much more straightforward. The combination of a quadrupole, a collision cell and a time of flight section (a Q-TOF instrument) even makes it possible to sequence peptides derived from the tryptic digestion of a protein. For all but the most abundant proteins in a blood spot we currently have to employ a purification step in order to pull out the protein of interest. But it is already possible to prepare subfractions of proteins using surface technology on a chip (SE [surface-enhanced] LDI TOF-MS). This technique is being used to identify biomarkers of a disease without any prior hypothesis. I think we can anticipate the possibility of detecting an increasing number of genetic diseases from a blood spot by analysis of the proteins.

DNA analysis is already in use as a second line test e.g. in deficiencies of medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain hydroxyacyl CoA dehydrogenase (LCHAD). DNA chip technology gives us a powerful tool for the detection of disorders for which there are a few common mutations, however, this is not the case for many disorders.

As the number of possibilities for screening increases, it will be important to look at the advantages and disadvantages very carefully for each disorder. In fact, the future should not be led by the technology but by a careful consideration of the power of the measurement to prevent disability and death.