Tandem Mass Spectrometric Analysis for Amino, Organic, and Fatty Acid Disorders in Newborn Dried Blood Spots

Abstract

Background: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. Methods: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in ∼1.9 min. Cutoffs for each marker were set at 6–13 SD above the population mean. Results: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. Conclusions: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.

Newborn screening for medium‐chain acyl‐CoA dehydrogenase deficiency: A global perspective

“…Results of both the questionnaire survey and literature review are summarized in Tables 1-4. In 985A >G homozygotes, octanoylcarnitine (C 8 -carnitine) levels fall 2-to 3fold in the interval between days 1-2 and days 6-10 of life (Oerton et al 2005;Phillips et al 2005;Pourfarzam et al 2001;Zytkovicz et al 2001). A similar trend is noted in MCADD individuals with other genotypes.…”

“…Of course, this broadened mutational spectrum also reflects the reality that MCADD newborn screening detects 2-fold to 3-fold more cases of MCADD than does clinical ascertainment, with a substantially higher number of other, milder mutations identified. For example, those mutations identified in four MS/MS NBS programmes and tabulated in OMIM are listed in Table 4 Wilcken et al 2002Wilcken et al , 2003Zytkovicz et al 2001;Waddell et al 2006;O. Bodamer, personal communication 2005).…”

Validation of MCADD newborn screening

“…The capability of tandem mass spectrometry (MS/MS) has opened the path for expanding NBS to a wider range of metabolic disorders including MCADD (3)(4)(5)(6)(7)(8)(9)(10). Although MCADD screening has been introduced in many NBS programs, it is still associated with unresolved questions (11,12).…”

Neonatal screening for glutaric aciduria type I: Strategies to proceed

“…Furthermore, a 5-carbon dicarboxylic acylcarnitine, can be detected by acylcarnitine profiling in dried blood spots using tandem mass spectrometry (MS/MS; Chace et al 2002;Naylor and Chace 1999;Schulze et al 2003;Zytkovicz et al 2001). Since glutaric aciduria type I fulfils some important criteria for inclusion in mass screening programmes (not detectable on clinical grounds at birth but prevention of severe handicap by early treatment), it has been successfully implemented in neonatal screening programmes of some countries, such as Australia, Austria, Denmark, parts of the USA, and Germany (Chace et al 2002;Naylor and Chace 1999;Roscher et al 2001;Schulze et al 2003;Wilcken et al 2003;Wiley et al 1999;Zytkovicz et al 2001).…”

“…Glutarylcarnitine (C 5 DC) is the diagnostic variable used for MS/MS-based neonatal screening of glutaric aciduria type I (Naylor and Chace 1999;Zytkovicz et al 2001). As a deuterium-labelled analytical standard for C 5 DC is not available, true quantification is not yet possible.…”