The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005.

North Carolina (NC) was the first US state to initiate universal tandem mass spectrometry (MS/MS) newborn screening. This began as a statewide pilot project in 1997 to determine the incidence and feasibility of screening for fatty acid oxidation, organic acid and selected amino acid disorders. The MS/MS analyses were done by a commercial laboratory and all follow-up and confirmatory testing was performed through the NC Newborn Screening (NBS) Program. In April 1999, the NC NBS Laboratory began the MS/MS analyses in-house. Between 28 July 1997 and 28 July 2005, 944,078 infants were screened and 219 diagnoses were confirmed on newborns with elevated screening results, for an overall incidence of 1:4,300. Ninety-nine infants were identified with fatty acid oxidation disorders, 58 with organic acidaemias and 62 with aminoacidopathies. Medium-chain acyl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency and disorders of phenylalanine metabolism were the most common disorders detected. Identification of affected infants has allowed retrospective testing of other family members, resulting in an additional 16 diagnoses. Seven neonates died from complications of their metabolic disorders/prematurity despite timely MS/MS screening. In addition, there were six infants who were not identified by elevated NBS results but who presented with symptoms later in infancy. The NC MS/MS NBS Program uses a two-tier system, categorizing results as either 'borderline' or 'diagnostic' elevated, for both the cutoffs and follow-up protocol. Infants with an initial borderline result had only a repeat screen. Infants with a diagnostic or two borderline results were referred for confirmatory testing. The positive predictive value of the NC MS/MS NBS for those infants requiring confirmatory testing was 53% for 2003 and 2004. The success of the NC MS/MS NBS Program in identifying infants with metabolic disorders was dependent on a comprehensive follow-up protocol integrating the public health laboratory and the academic metabolic centres.

Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.

Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3-hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism associated with this metabolite. Ten of these 20 infants had significant concentrations of both 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in their urine, suggestive of 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency. Four of these 10 were infants whose abnormal metabolites were found to be of maternal origin. Of 8 patients with probable 3-MCC deficiency, 7 have been tested and found to have the enzyme deficiency confirmed in lymphoblasts or cultured fibroblasts; one of these 7 infants had only marginally decreased 3-MCC activity in lymphocytes but deficient 3-MCC in fibroblasts. We estimate the incidence of 3-MCC deficiency at 1:64000 live births in North Carolina. We conclude that MS/MS newborn screening will detect additional inborn errors of metabolism, such as 3-MCC deficiency, not traditionally associated with newborn screening. The evaluation of newborns with two abnormally elevated C5OH levels on MS/MS newborn screening should include, at least, urine organic acid analysis by capillary GC-MS and a plasma acylcarnitine profile by MS/MS. Long-term follow-up is needed to determine the outcome of presymptomatically diagnosed patients with 3-MCC deficiency by MS/MS newborn screening.