Expanded newborn screening by mass spectrometry: New tests, future perspectives

Abstract

Tandem mass spectrometry (MS/MS) has become a leading technology used in clinical chemistry and has shown to be particularly sensitive and specific when used in newborn screening (NBS) tests. The success of tandem mass spectrometry is due to important advances in hardware, software and clinical applications during the last 25 years. MS/MS permits a very rapid measurement of many metabolites in different biological specimens by using filter paper spots or directly on biological fluids. Its use in NBS give us the chance to identify possible treatable metabolic disorders even when asymptomatic and the benefits gained by this type of screening is now recognized worldwide. Today the use of MS/MS for second-tier tests and confirmatory testing is promising especially in the early detection of new disorders such as some lysosomal storage disorders, ADA and PNP SCIDs, X-adrenoleucodistrophy (X-ALD), Wilson disease, guanidinoacetate methyltransferase deficiency (GAMT), and Duchenne muscular dystrophy. The new challenge for the future will be reducing the false positive rate by using second-tier tests, avoiding false negative results by using new specific biomarkers and introducing new treatable disorders in NBS programs.

Applying targeted next generation sequencing to dried blood spot specimens from suspicious cases identified by tandem mass spectrometry-based newborn screening

“…Compared to the sophisticated TMS applications in expanded NBS in developed countries [1,3,4], China has been making great efforts to explore, evaluate, and implement TMS screening since 2003 [18,21,22]. At present, China has an estimated national coverage of 20%, concentrated in well-developed provinces and cities [21,22].…”

“…On the other hand, insufficient sample quantity as well as unqualified sample preparation (which takes 16% of sort-out cases), probably owing to sample contamination or degradation (data not shown), also resulted in the rejection of several cases from enrollment. Nevertheless, underdiagnosis might still be inevitable, even when all of the confirmation/diagnosis-insufficient cases are included since the false-negativity of primary TMS screening was not taken into account [1,4,7]. Second, IEMs might be caused by variants located outside of exons, and thus are not detectable by TNGS [29,30].…”

“…Via the detection of amino acids and acylcarnitines, up to 40 IEMs -mainly categorized into amino acid, organic acid, and fatty acid disorders -are able to be identified in a single 2-3 min run [2]. Broader applications on other IEMs and genetic diseases such as lysosomal storage disorders and severe combined immune deficiency were also reported [2][3][4][5].…”

“…[2,3,[6][7][8][9]. Although series of tests and examinations are available, these combined results may still not be pathogenically differential or diagnostically indicative; thus, more definitive tests such as enzymatic or genetic assays are usually introduced to reduce unambiguity in diagnosis [1,4,6].…”

Mass spectrometry or immunoassay: est modus in rebus

“…LC-MS/MS is currently considered the method of choice for inherited metabolic disorder [8] and steroid hormone assay, especially in cases requiring accurate measurement at very low concentrations [9]. In the face of the strengths of LC-MS/MS, there are also some weaknesses, including high initial instrumental costs (albeit with the potential for important cost-saving), serial-access operation, need for highly skilled personnel, limited CE-IVD approved reagents and kits, and limited sample throughput [3].…”