MSUD Nutrition Management Guidelines
First Edition
February 2013, v.1.46
Current version: v.1.58
Updated: May 2014
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Introduction to Guidelines

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by branched-chain α-ketoacid dehydrogenase (BCKD)deficiency. In the classical form, where there is less than 3% residual enzyme activity, symptoms occur soon after birth. In the untreated neonate, on a normal intake of protein, the odor of maple syrup may be detected in the cerumen as early as 12-24 hours, and in the urine by 48-72 hours, after birth. Elevated plasma concentrations of the branched-chain amino acids (BCAA), leucine (LEU), isoleucine (ILE), valine (VAL) and alloisoleucine (allo-ILE), as well as a generalized disturbance of plasma amino acid concentration ratios are present by 12-24 hours of age; elevated branched-chain α-ketoacids (BCKA) and generalized ketonuria, irritability, and poor feeding by 24-72 hours; deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" by 4-5 days; and coma and central respiratory failure that may occur by 7-10 days. Other phenotypes with various degrees of partial enzyme activity include the intermediate, thiamin-responsive, and intermittent forms of MSUD that can lead to severe metabolic intoxication and encephalopathy with sufficient catabolic stress. Characteristics of the different phenotypes are in TABLE #1, MSUD Phenotypes. Further information can be found at:

TABLE 1 - MSUD Phenotypes


Clinical Symptoms

(prior to treatment)


% BCKD activity


Neonatal onset, poor feeding, lethargy, altered tone, ketoacidosis, seizures. Symptoms often present prior to learning NBS results. Prenatal testing in at-risk siblings can allow dietary intervention at birth. Nearly all due to mutations in the E1 BCKD subunits

↑↑ allo-ILE, BCAA, BCKA

0 -2


Failure to thrive, ketoacidosis and developmental delay; classical symptoms can occur during catabolic illness/stress

↑ allo-ILE, BCAA, BCKA

3 - 30


Normal early development, episodic ataxia/ketoacidosis, severe symptoms may be precipitated by catabolic illness/stress. May be missed by MS/MS NBS

Normal BCAA, BCKA when asymptomatic

5 - 20

Thiamin (B1) responsive

Similar to intermediate. Often due to mutations in E2 BCKD subunit

↑ allo-ILE, BCAA, BCKA ↓BCKA and/or BCAA with thiamin therapy

2 - 40

Lipamide dehydrogenase deficiency

Normal neonatal period, failure to thrive, hypotonia, lactic acidosis, developmental delay, movement disorder. Due to mutations in the E3 BCKD subunit - a component of both pyruvate dehydrogenase and α-ketoglutarate dehydrogenase

Moderate BCAA and BCKA, ↑ α-ketoglutarate, pyruvate

0 - 25

Newborn Screening

The analytes used as markers for mass spectrometry (MS/MS) newborn screening for MSUD are LEU (LEU and its isomers ILE, allo-ILE) and VAL. The ratio of LEU to phenylalanine helps distinguish possible MSUD from an infant on parenteral/supplemental amino acid or generalized aminoacidemia.  Another analyte, hydroxyproline (elevated in hydroxyprolinemia), has the same mass-to-charge ratio as the LEU isomers and may (rarely) lead to false-positive results (L.1).


Confirmatory Testing

Newborn screening alone is not diagnostic. Those with a positive newborn screen require follow-up biochemical testing and clinical evaluation for confirmation.

  • Plasma amino acid analysis: BCAA and presence of allo-ILE.
  • Urine organic acid analysis: presence of BCKA. The urine DNPH reaction: presence of α-ketoacids and ketones


MSUD is inherited as an autosomal recessive disorder. Carriers of MSUD have not shown any signs/symptoms of impaired BCAA catabolism. The genes encoding the various catalytic subunits/components (E1a, E1b, E2, E3) have been mapped to chromosome loci: 19q13.1-13.2; 6q14; 1p31; and 7q31-32, respectively. In a total of 78 cell lines from MSUD subjects, the large majority had mutations in the E1 subunits. A common mutation among the Old Order Mennonites is Y393N, a point mutation in the E1a subunit. See: