A DANISH THREE-YEAR PROSPECTIVE TRIAL OF NEWBORN SCREENING FOR INBORN ERRORS OF METABOLISM USING TANDEM MASS SPECTROMETRY

Objectives: To evaluate prospective supplemental tandem mass spectrometry (MS/MS) screening of newborns for galactosemia and inborn errors of metabolism (IEM) associated with amino acids and acylcarnitines.

Methods: Subjects were recruited in Denmark and the Faroe Islands by an informed consent procedure in conjunction with the established newborn screening program for PKU, hypothyroidism, and toxoplasmosis. 145000 were screened for amino acids and acylcarnitines, and 95000 of these were additionally screened for galactosemia. The birth cohort was 195000. Results: Nineteen patients with non-PKU IEM were diagnosed (1:7600) and there were 79 false-positives (0.06%). The disorders comprised deficiencies of medium-chain acyl- CoA dehydrogenase (MCAD) (11), 3-methylcrotonyl-CoA carboxylase (3), holocarboxylasesynthase (1), 3-methylglutaconyl-CoA hydratase (1), isobutyryl-CoA dehydrogenase (1), carnitine transporter (1), and galactosemia (1). In addition, 11 newborns with disorders within the supplemental screening panel were diagnosed by selective screening because of older affected sibs or early presention (urea cycle disorders, multiple acyl-CoA dehydrogenation deficiency). The screening prevalence of MCAD deficiency was increased 4-fold over the clinical detection rate of the previous decade. In the Faroese population, the screening prevalence was ca. 1:1100 due to the highly prevalent deficiencies of holocarboxylase synthase and carnitine transporter. The false-positives were grouped on few disorders and could be reduced by cutoff adjustments. No undesirable effects of the supplemental screening program were registered.

Conclusion: The addition of acylcarnitines to the existing screening panel increases the presymptomatic detection of IEM, chiefly MCAD deficiency and disorders associated with increased levels of betahydroxyisovalerylcarnitine (deficiencies of 3- methylcrotonyl-CoA carboxylase, holocarboxylasesynthase, and 3-methylglutaconyl- CoA hydratase). The amino acid panel did not provide diagnoses other than PKU.