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Letters to the Editor |
1 Laboratory Becker, Olgemöller and Colleagues, Munich, Germany
2 Department of General Pediatrics University Children’s Hospital, Heinrich-Heine-University, Düsseldorf, Germany
3 Research Center, Departement of Biochemical Genetics and Molecular Biology, von Hauner Children’s Hospital, Ludwig-Maximilians-Universität, Munich, Germany
4 Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charité University Medical Center, Berlin, Germany
aAddress correspondence to this author at: Laboratory Becker, Olgemöller & Colleagues, Ottobrunnerstr. 6, D-81737, Munich, Germany, Fax + 49/89/544 654 10, E-mail r.fingerhut{at}labor-bo.de
To the Editor:
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 leucine" (leucine + isoleucine + alloisoleucine + hydroxyproline) in dried blood spots. These 4 isobaric amino acids cannot be separated by routine screening methods. The tentative diagnosis has to be confirmed by measuring BCAA concentrations in plasma. The recall rate for MSUD in Germany is 
0.01% (calculated from >1.5 million newborns in the Bavarian and Berlin screening laboratory).
We compared total leucine concentrations in dried blood and leucine concentrations in plasma during confirmation diagnosis between subjects attributed retrospectively to classic or variant MSUD. Data on the patients with classic MSUD have been published recently(2). Data are presented as ranges and/or mean (SD). Data analysis was performed by SPSS-12 (SPSS Inc). The Wilcoxon rank sum test (Mann–Whitney U-test) was used to compare differences between the 2 groups of patients. P < 0.05 was considered statistically significant.
In Table 1
, we present laboratory data of 19 newborns who screened positive for MSUD in Germany and Austria from 1999 to 2005. MSUD was suspected by detecting increased total leucine concentrations in dried blood spots collected between the second and eighth day of life. Total leucine concentrations in newborns suffering from classic MSUD (subjects C1–C10) were significantly higher than concentrations in newborns who were later attributed to a variant form (subjects V1–V9) [1240 (557) µmol/L vs 549 (267) µmol/L, P = 0.003]. Because of high variance, however, it was impossible to reliably discriminate between classic and variant MSUD by NBS results. In confirmation diagnosis by amino acid analysis performed on day 4–23, differentiation was unambiguous, with a mean plasma leucine concentration of 447 (161) µmol/L in variant MSUD in contrast to 2100 (791) µmol/L in classic MSUD (P = 0.001). Importantly, no newborn with variant MSUD needed emergency management.
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Our data show that an unambiguous discrimination between variant and classic MSUD is impossible by NBS. Therefore the detection of any elevation of total leucine in NBS requires immediate referral to a specialized metabolic unit or a local pediatrician/physician (in consultation with a metabolic specialist) to confirm the diagnosis by quantitative determination of plasma amino acids and to institute treatment. Measurement of plasma leucine concentrations by amino acid analysis clearly differentiates between classic and variant MSUD, which is important for choosing the proper treatment. Most likely, leucine and isoleucine concentrations in early postnatal life are crucially influenced by the extent of neonatal protein catabolism, which might differ considerably between individuals, and may account for the reported missed cases of variant MSUD(3).
Oglesbee et al.(4) recently described a method to quantify the isobaric amino acids leucine, isoleucine, alloisoleucine, and hydroxyproline as a second-tier test from the initial NBS dried blood spots. Only samples with both increased total leucine and increased alloisoleucine would lead to further metabolic workup. This approach appears promising for further reducing false-positive rates. Even with this improvement, however, discrimination between classic and variant MSUD may not be possible from the NBS results(5).
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest.
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: The study was carried out as part of METABNET (Network for Genetic Metabolic Diseases Detectable by Newborn Screening) funded by the German Federal Ministry of Education and Research (BMBF), grant no. 01GM0305.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Acknowledgments: The authors very much appreciate the support of the following colleagues: M. Lindner, V. Konstantopoulou (Heidelberg), J. Baumkötter (München), I. Knerr (Erlangen), R. Ratschmann (Wien), C. Korenke (Oldenburg), T. Marquardt, (Münster). Informed consent for the analysis was obtained from a parent of the patients. This study was approved by the Institutional Review Board of the Heinrich-Heine University.
Footnotes
1 Nonstandard abbreviations: MSUD, maple syrup urine disease; NBS, newborn screening; BCAA, branched-chain amino acid; ESI-MS/MS, electrospray ionization–tandem mass spectrometry. 
References
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