Newborn screening (NBS) using tandem mass spectrometry (MS/MS) permits detection of neonates with Glutaric Aciduria-Type II (GA-II). We report follow-up of positive GA-II screens by the New England Newborn Screening Program. METHODS: 1.5 million infants were screened for GA-II (Feb 1999-Dec 2012). Specialist consult was suggested for infants with two or more acylcarnitine elevations suggestive of GA-II. RESULTS: 82 neonates screened positive for GA-II, 21 weighing > 1.5 kg and 61 weighing < /= 1.5 kg. Seven (one weighing < 1.5 kg), were confirmed with GA-II. Four of these had the severe form (died < 1 week). The other three have a milder form and were identified because of newborn screening. Two (ages > 5 years) have a G-Tube in place, had multiple hospitalizations and are slightly hypotonic. The third infant remains asymptomatic (9 months old). Two GA-II carriers were also identified. The remaining positive screens were classified as false positives (FP). Six infants ( > 1.5 kg) classified as FP had limited diagnostic work-up. Characteristics and outcomes of all specimens and neonates with a positive screen were reviewed, and marker profiles of the cases and FP were compared to identify characteristic profiles. CONCLUSION: In addition to the severe form of GA-II, milder forms of GA-II and some GA-II carriers are identified by newborn screening. Some positive screens classified as FP may be affected with a milder form of the disorder. Characteristic GA-II profiles, quantified as GA-II indexes, may be utilized to predict probability of disorder and direct urgency of intervention for positive screens.

OBJECTIVE: The objective of this study is to develop an isotope dilution liquid chromatography tandem mass spectrometry assay to screen for hepatorenal tyrosinemia (HT) from newborn filter paper samples using pooled extracts to increase high throughput screening. DESIGN AND METHODS: Succinylacetone (SUAC), the marker for HT, was extracted from dried blood spots with the formation of the hydrazone derivative of SUAC; up to eight sample extracts were pooled and the SUAC-derivative was analyzed by mass spectrometry methods with an injection-to-injection time of one minute. If any pooled sample extract screened positive, then the samples comprising the pooled sample were assayed individually. RESULTS: Two newborn infants were identified with high levels of SUAC (7 and 23muM) and later confirmed to have HT. Three older children whose initial filter paper samples were taken at 195days to 614days of age with elevated SUAC (range 4.9-5muM) were identified; one of the three had clinical signs of HT and was placed on treatment (diagnosis of the other two are unavailable). CONCLUSION: MS/MS analysis of pooled dried blood sample extracts permits sensitive, reduced instrumental analytical time and increase high throughput screening for HT. Elsevier Inc. All rights reserved.

OBJECTIVE: Our goal was to describe the clinical spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by routine newborn screening and assess factors associated with elevations of octanoylcarnitine in newborns and characteristics associated with adverse clinical consequences of medium-chain acyl-CoA dehydrogenase deficiency. METHODS: The first 47 medium-chain acyl-CoA dehydrogenase deficiency cases detected by the New England Newborn Screening Program were classified according to initial and follow-up octanoylcarnitine values, octanoylcarnitine-decanoylcarnitine ratios, medium-chain acyl-CoA dehydrogenase genotype, follow-up biochemical parameters, and feeding by breast milk or formula. RESULTS: All 20 patients who were homozygous for 985A-->G had high initial octanoylcarnitine values (7.0-36.8 microM) and octanoylcarnitine-decanoylcarnitine ratios (7.0-14.5), whereas the 27 patients with 0 to 1 copy of 985A-->G exhibited a wide range of octanoylcarnitine values (0.5-28.6 microM) and octanoylcarnitine-decanoylcarnitine ratios (0.8-12.7). Initial newborn octanoylcarnitine values decreased by days 5 to 8, but the octanoylcarnitine-decanoylcarnitine ratio generally remained stable. Among 985A-->G homozygotes, breastfed newborns had higher initial octanoylcarnitine values than newborns who received formula. Adverse events occurred in 5 children, 4 985A-->G homozygotes and 1 compound heterozygote with a very high initial octanoylcarnitine: 2 survived severe neonatal hypoglycemia, 1 survived a severe hypoglycemic episode at 15 months of age, and 2 died as a result of medium-chain acyl-CoA dehydrogenase deficiency at ages 11 and 33 months. CONCLUSION: Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency has detected cases with a wide range of genotypes and biochemical abnormalities. Although most children do well, adverse outcomes have not been entirely avoided. Assessment of potential risk and determination of appropriate treatment remain a challenge.

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 approximately 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.