Newborn screening (NBS) for inborn errors of metabolism (IEM) began over 50 years ago with Robert Guthrie’s bacterial inhibition test to detect phenylketonuria by means of elevated phenylalanine concentrations in dried blood spots collected during the first few days of life [1
]. During the ensuing period covering more than 30 years, a few additional tests for conditions that satisfied criteria published by Wilson and Jungner in 1968 [2
] were added to the panel. For the most part, by the mid-1990s, most programs in the United States were screening for only a few conditions, which included phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia and galactosemia. At that time, the concept of multiplex testing was introduced using tandem mass spectrometry (MS/MS) [3
]—a method that detects multiple acylcarnitines and amino acids simultaneously and recognizes more than 30 IEM [5
]. The widespread adoption of this practice over the subsequent decades has dramatically changed the landscape of NBS. Initially, there was confusion and concern regarding the number of conditions that multiple analyte testing by MS/MS was potentially able to detect. Furthermore, many of the conditions detectable by MS/MS do not satisfy the Wilson and Jungner criteria. In an attempt to bring some order to this somewhat chaotic situation, the Health Resources and Services Administration (HRSA), an agency of the U.S. Department of Health and Human Services, requested assistance from the American College of Medical Genetics (ACMG). The ACMG formed a Committee to conduct a systematic evaluation of newborn screening programs and reviewed over 80 conditions for possible inclusion in a universal recommended panel that NBS programs could regard as a standard. The result was a report that recommended 29 primary targets (the “core disorders”) for universal screening, subsequently referred to as the ‘recommended uniform screening panel’ (RUSP) [8
]. The same report identified a further 26 conditions, referred to as secondary conditions, that expanded NBS may detect in addition to those on the RUSP [8
]. The ACMG Committee established more stringent criteria for inclusion of conditions to the RUSP and was later encompassed by the U.S. Department of Health and Human Services Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) [10
]. This committee has subsequently recommended the inclusion of severe combined immune deficiency (SCID), Critical Congenital Heart Defects (CCHD), and most recently Pompe Disease (Glycogen Storage Disease-II), Hurler Syndrome (MPS I) and X-linked adrenoleukodystrophy (X-ALD) to the RUSP, making a total of 34 core conditions as of the time of writing.
The inclusion of Pompe and Hurler, both of which are examples of lysosomal storage disorders (LSDs), to the RUSP is proving to be challenging and controversial [11
]. Part of the driving force for the inclusion of LSDs is the development of promising new treatment options such as enzyme replacement therapy and hematopoietic stem cell transplantation, as well as the development of new screening tests based on the measurement of enzymatic activity [13
]. Another contributing factor has been the advocacy of special interest groups that have successfully lobbied the legislators in certain state programs in the US to mandate screening for LSDs regardless of the SACHDNC procedures and recommendations. Thus, New York was compelled to screen for Krabbe disease [15
], while Illinois and Missouri issued mandates to screen for Krabbe and five additional LSDs prior to the addition of any LSDs to the RUSP [16
Programs that are currently on the cusp of screening for at least the two LSDs currently on the RUSP (Pompe and Hurler disorders) are faced with a choice between the few viable methods that are currently in use in NBS programs. The purpose of this review is to compare objectively the options that are applicable to high throughput measurement of multiple enzymes for the detection of LSDs, based on currently available and published data.