Maple Syrup Urine Disease: Newborn Screening Fails to Discriminate between Classic and Variant Forms

Abstract

Maple syrup urine disease (MSUD)1 (OMIM 248600) is an inborn error of metabolism detectable by newborn screening (NBS). Deficiency of the branched-chain 2-keto acid dehydrogenase leads to the accumulation of branched-chain amino acids (BCAA) leucine, valine, isoleucine, and alloisoleucine. About 75% of MSUD patients have the severe classic form (<2% enzyme activity). They develop a severe encephalopathic crisis with deep coma, mostly during the second week of life, owing to very high concentrations of BCAAs (≫1000 μmol/L leucine). The remainder have milder variant forms (2%–40% enzyme activity) with lower concentrations of BCAAs (≪1500 μmol/L leucine) and later onset or absence of cerebral symptoms(1). Severely ill newborns require urgent lowering of branched-chain compounds followed by lifelong semisynthetic diet with reduced intake of BCAAs. Because even subjects with a mild form of MSUD are at risk of acute metabolic decompensation during stressful situations, they also may benefit from early presymptomatic diagnosis by NBS. Whereas newborns with classic MSUD need emergency management including intensive care and occasionally extracorporeal detoxification, this expensive treatment is not necessary in newborns with variant MSUD. We performed the present study to find out if classic and variant MSUD can be discriminated by NBS so that adequate treatment may be initiated when receiving the result of a tentative diagnosis of MSUD in NBS. Since 2002, electrospray ionization–tandem mass spectrometry (ESI-MS/MS)–based NBS has been available in Germany for every newborn. NBS for MSUD is performed by measuring the concentration of “total …