Abstract
The principles of newborn screening for inherited metabolic diseases were set in the 1960s following Robert Guthrie’s demonstration that phenylketonuria (PKU) could be diagnosed by analysis of phenylalanine levels in a filter paper bloodspot collected just after birth. 1 A number of additional conditions including congenital hypothyroidism and congenital adrenal hyperplasia were added as they fulfilled the inclusion criteria defined by Wilson and Jungner 2 for disease frequency and treatability. At around this time, a number of additional metabolic diseases were being identified including amino acid, lysosomal and organic acid disorders which were considered to be too rare, required prohibitively complex analysis for diagnosis or were untreatable and therefore not suitable for newborn screening programs under the Wilson and Jungner criteria. Organic acid analysis by gas chromatography-mass spectrometry to diagnose organic acid disorders at this time was only available in two laboratories in the UK and this was generally felt to be sufficient as we had such rare diseases to contend with.
With this scenario in mind, and armed only with a couple of ageing gas chromatographs with flame ionization detectors in the Sheffield Children’s Hospital clinical chemistry laboratory, but with mass spectrometric peak identification confirmation available in Rodney Pollitt’s nearby laboratory across town, we embarked on a study to determine whether organic acid analysis was an appropriate assay for the clinical laboratory in a tertiary care paediatric centre. Initially, the cases identified for inclusion in this study represented the low hanging fruit as the only cases of organic acid disorders in the literature at that time had profound metabolic decompensation including recurrent metabolic acidosis, ketonuria, hypoglycaemia and the unusual odour that was known to be associated with isovaleric acidaemia. Yes, in those days we would sniff the urine prior to extraction! The diagnostic yield from this study was sufficiently impressive that it merited an article which was published in the Annals in 1984. 3 We recommended that this assay was appropriate for metabolic disease diagnosis and should be available in all tertiary care paediatric facilities. Over the years this has turned out to be the case and many paediatric facilities across the UK (and from my later perspective across the pond) now have ready access to organic acid analysis using bench-top gas chromatography with mass selective detection. And indeed, the range of clinical phenotypes for organic acid disorders is now so broad that it has become a first-line metabolic test meriting centre field in all standard text books and diagnostic protocols.
As we expanded our horizons with expansion of organic acid analysis in Sheffield, we started to recognize a cohort of infants who generally presented with recurrent hypoglycaemia (sometimes fatal) in whom the organic acid profile revealed medium chain dicarboxylic acids and acylglycine abnormalities similar to those described seminally by Niels Gregersen and his colleagues in Denmark; a pattern that suggests a defect of medium-chain fatty acid metabolism. 4,5 These infants were eventually demonstrated to have medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. 6 The frequency with which this defect was found appeared, from the many case reports of symptomatic patients, to be of the same order at which PKU was found in the general population. Coupled to this likely population frequency and the eventual recognition that MCAD deficiency could be easily treated by preventing fasting, the initial seeds of MCAD as a candidate for newborn screening were sown. At that time we knew of several biomarkers for MCAD deficiency, all of which were present in blood samples from affected newborns. However, none were yet amenable to whole population screening. 7,8 The Annals published the first paper showing that biomarkers for MCAD deficiency could be measured in newborn blood spots but, unfortunately, those biomarkers required analytical processes that were unsuitable for whole population screening. 9 MCAD deficiency has subsequently been proven to be as common as PKU and whole population screening is fully justified.
It was the subsequent seminal work of David Millington’s group at Duke University that identified blood spot octanoylcarnitine as a suitable biomarker for the early detection of MCAD deficiency. 10 Measurement of C8 carnitine can be performed rapidly and with great sensitivity using tandem mass spectrometry. This group also identified acylcarnitine biomarkers that could be simultaneously measured for many of the other fatty acid oxidation defects and some organic acid disorders opening the door for newborn screening on a broad scale for multiple metabolic disorders. This process already takes place in many countries and my guess is that the UK program will expand beyond MCAD deficiency very soon and begin to include other organic acid and fatty acid oxidation defects. The rest, as they say, is history.
Declarations of conflicting interests
None declared.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethical approval
Not required.
Guarantor
Michael J Bennett.
Contributorship
Michael J Bennett is the sole author.