Tandem mass spectrometry has been successfully developed for the detection and quantification of acylcarnitines and amino acids in dried bloodspots from neonates for the potential diagnosis of 33 inherited biochemical defects, including phenylketonuria (1). Twenty-two of these disorders are recognized by acylcarnitine analysis. The majority of these disorders are characterized by more than one clinical phenotype (2). This increasing phenotypic complexity is compounded by the existence of acylcarnitine profiles that are not necessarily specific for a single disease.
Some examples of diseases that are associated with either identical or overlapping acylcarnitine profiles are as follows:
Actually, there are only three disorders for which the acylcarnitine profile is completely disease-specific: MCAD, Glutaric Aciduria type I, and Malonic Aciduria.
Although the distinction between diseases which have similar or identical acylcarnitine profiles is often aided by knowledge of the clinical course in that infant or child, that information will not usually be available for the interpretation of the abnormal newborn screening result prior to symptom onset.
The recent descriptions of newly characterized inherited disorders that have the same blood-spot acylcarnitine profile (3,4) emphasize the need for additional documentation to accurately diagnose the specific disorder so that appropriate management can be implemented.
Similarly, there have been in vitro demonstrations of distinct acylcarnitine profiles for different clinical phenotypes of the same disease, even with the same mutation (VLCAD, LCHAD, ETF-DH) (5, 6). The acylcarnitine profiles from neonatal blood spots do not show any correlation with these clinical phenotypes.
Finally, not all of the diseases that are said to be potentially detectable by tandem acylcarnitine analysis have actually been observed in neonates. Experience now indicates that it is also occasionally possible to have a normal newborn screen in some cases of LCHAD and SCAD deficiencies. More information is required to determine the extent of both false negatives and false positives for some of these disorders. This may require a second analysis after ~ 2 weeks of life.
Tandem mass spectrometry analysis of acylcarnitine profiles in the neonate is a major step forward in neonatal screening. The potential for expansion to other biochemical disorders (steroids, bile acids, etc.) is possible and the cost should not increase significantly with the addition of new disorders.
Tandem screening should be regarded as a more sophisticated and comprehensive "screen" which can effectively indicate the presence of many inherited disorders. However, the existence of several diseases with the same neonatal acylcarnitine profile and the fact that the neonatal blood profile can not distinguish clinical phenotypes of the same disease emphasize the requirement for additional sophisticated and specific testing to provide accurate diagnosis, counseling, and appropriate treatment.