Maple-syrup urine disease (MSUD) is an inborn error of metabolism caused by the deficiency of the branched-chain-ketoacid dehydrogenase (BCKDH) complex. The BCKDH complex is involved in the metabolism of the branched-chain amino acids (BCAA): isoleucine (Ile), leucine (Leu), and valine (Val). Classic MSUD presents in the neonate with feeding intolerance, failure to thrive, vomiting, lethargy, and maple-syrup odor to urine and cerumen. If untreated, it progresses to irreversible mental retardation, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death.
MSUD is a pan-ethnic condition but is most prevalent in the Old Order Mennonite community in Lancaster, Pennsylvania with an incidence there of 1:760 live births. The incidence of MSUD is approximately 1:200,000 live births in the general population.
Newborn screening includes the measurement of BCAA (Leu, Ile, and Val), which are elevated in MSUD. However, unaffected infants receiving total parenteral nutrition frequently have increased levels of BCAA, a situation that often triggers unnecessary follow-up investigations. Abnormal concentrations of allo-isoleucine (Allo-Ile) are pathognomonic (=indicative) for MSUD. The determination of Allo-Ile (second-tier testing) in the same newborn screening specimens that reveals elevated BCAA allows for positive identification of patients with MSUD and differentiation from BCAA elevations due to dietary artifacts, reducing the occurrence of false-positive newborn screening results.
Treatment of MSUD aims to normalize the concentration of BCAA by dietary restriction of these amino acids. BCAA are essential amino acids, which require frequent adjustment of the dietary treatment. Dietary monitoring is accomplished by regular determination of BCAA and Allo-Ile concentrations.
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2. Simon E, Fingerhut R, Baumkotter J, Konstantopoulou V, Ratschmann R, Wendel U: Maple syrup urine disease: Favorable effect of early diagnosis by newborn screening on the neonatal course of the disease. J Inherit Metab Dis. 2006;29:532-537 
3. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI: Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics. 2002;109:999-1008 
4. Strauss KA, Puffenberger EG, Carson VJ: Maple syrup urine disease. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of Washington, Seattle; 2006. Updated April 23, 2020. 
Allo-isoleucine is nearly undetectable in individuals not affected by maple-syrup urine disease (MSUD). Accordingly, its presence is diagnostic for MSUD, and its absence is sufficient to rule-out MSUD.
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