Abstract
Maple syrup urine disease (MSUD) leads to severe neurological deterioration unless diagnosed early and treated immediately. We have evaluated the effectiveness of 11 years of MSUD newborn screening (NBS) in the Netherlands (screening >72 hours, referral if both total leucine (Xle) and valine ≥400 μmol/L blood) and have explored possibilities for improvement by combining our data with a systematic literature review and data from Collaborative Laboratory Integrated Reports (CLIR). Dutch MSUD NBS characteristics and accuracy were determined. The hypothetical referral numbers in the Dutch population of additional screening markers suggested by CLIR were calculated. In a systematic review, articles reporting NBS leucine concentrations of confirmed patients were included. Our data showed that NBS of 1 963 465 newborns identified 4 MSUD patients and led to 118 false‐positive referrals (PPV 3.28%; incidence 1:491 000 newborns). In literature, leucine is the preferred NBS parameter. Total leucine (Xle) concentrations (mass‐spectrometry) of 53 detected and 8 false‐negative patients (sampling age within 25 hours in 3 patients) reported in literature ranged from 288 to 3376 (median 900) and 42 to 325 (median 209) μmol/L blood respectively. CLIR showed increasing Xle concentrations with sampling age and early NBS sampling and milder variant MSUD phenotypes with (nearly) normal biochemical profiles are causes of false‐negative NBS results. We evaluated the effect of additional screening markers and established the Xle/phenylalanine ratio as a promising additional marker ratio for increasing the PPV, while maintaining high sensitivity in the Dutch MSUD NBS.
Highlights
Maple syrup urine disease (MSUD, MIM ID 248600) is a rare autosomal recessively inherited inborn error of metabolism caused by deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD; E.C.1.2.4.4) complex
The preferred strategy for maple syrup urine disease (MSUD) newborn screening (NBS) is using total leucine. aLikely MS/MS (Xle) as single identification parameter, in some studies combined with Val
The lowest Xle concentration in the four confirmed MSUD patients in the Netherlands was 697 μmol/L blood, and in literature all classic MSUD patients screened by MSUD patients.5-8 The introduction of tandem mass-spectrometry (MSMS) had Xle concentrations of 524 μmol/L blood or higher, which is above our Xle cut-off value (COV)
Summary
Maple syrup urine disease (MSUD, MIM ID 248600) is a rare autosomal recessively inherited inborn error of metabolism caused by deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD; E.C.1.2.4.4) complex. Deficient BCKD complex activity leads to the accumulation of the branched-chain amino acids (BCAAs): leucine (Leu), valine (Val), and isoleucine (Ile) of which Leu has acute neurotoxic effects. Based on the clinical presentation MSUD can be divided into five phenotypes: a classic phenotype, three milder phenotypic variants (intermediate, intermittent, and thiamine-responsive), and a fifth phenotype caused by dihydrolipoyl dehydrogenase (E3)-deficiency.[1] Patients with the classic phenotype of MSUD have less than 3% residual BCKD complex activity and a clinical onset typically in the first weeks of life. These patients can experience severe metabolic decompensations with increased Leu concentrations.[1]
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