Maple syrup urine disease

Lindsay C Burrage MD PhD (Dr. Burrage of Baylor College of Medicine has no relevant financial relationships to disclose.)
Philippe Campeau MD (Dr. Campeau of Baylor College of Medicine has no relevant financial relationships to disclose.)
Brendan H Lee MD PhD (Dr. Lee of Baylor College of Medicine received clinical research funding from Hyperion and consultation fees from Agios and Biomarin.)
AHM M Huq MD PhD, editor. (Dr. Huq of Wayne State University has no relevant financial relationships to disclose.)
Originally released December 28, 1993; last updated March 24, 2016; expires March 24, 2019

This article includes discussion of maple syrup urine disease, branched-chain ketoacid dehydrogenase deficiency, BCKD deficiency, branched-chain alpha-ketoaciduria, branched-chain ketoaciduria, MSUD, classical maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, and thiamine-responsive maple syrup urine disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Maple syrup urine disease is an inborn error of branched-chain ketoacid metabolism that presents classically with metabolic distress in newborns, although milder presentations exist. Branched-chain amino acids (leucine, isoleucine, and valine) and their ketoacids are increased in the blood, and the intake of these amino acids must be controlled. In this article, the authors detail novel approaches to the treatment of maple syrup urine disease, such as the experimental use of phenylbutyrate to prevent the inactivation of the implicated dehydrogenase complex.

Key points

 

• Inborn errors of metabolism should be suspected in newborns and infants with unexplained encephalopathies.

 

• Soon after birth, maple syrup urine disease classically presents with an encephalopathy accompanied by abnormal movements such as pedaling, ketonuria, and urine with a burnt sugar odor.

 

• The metabolic defect is in the branched-chain keto acid dehydrogenase complex, and dietary branched-chain amino acids (leucine, isoleucine, and valine) should be restricted and monitored.

 

• Novel therapies investigated include hepatocyte transplantation, drugs to counter oxidative stress, norleucine, and phenylbutyrate to prevent the inactivation of the dehydrogenase complex.

Historical note and terminology

A hereditary encephalopathy with sweet-smelling urine was described in 1954 (Menkes et al 1954), and shortly thereafter elevations in plasma branched-chain amino acids and their keto acids in the urine were noted (Westall et al 1957; Menkes 1959). A defect in branched-chain alpha-ketoacid dehydrogenase was then identified (Dancis et al 1960). Dietary therapy was established, and newborn screening programs were implemented (Westall 1963; Snyderman et al 1964). The genes encoding the proteins that form the complex were subsequently identified.

Component

Subunit

Mutations

in MSUD

MSUD

type

Gene

Reference for cloning or identification

Branched-chain alpha-ketoacid decarboxylase

E1-alpha

Yes

IA

BCKDHA

(Tiu et al 1988)

Branched-chain alpha-ketoacid decarboxylase

E1-beta

Yes

IB

BCKDHB

(Nobukuni et al 1990)

Branched-chain dihydrolipoamide acyltransferase

E2

Yes

II

DBT

(Danner et al 1989a; Danner et al 1989b)

Dihydrolipoamide dehydrogenase

E3

Yes

III

DLD

(Otulakowski and Robinson 1987)

BCKD kinase

 

No

N/A

BCKDK

(Popov et al 1992)

BCKD phosphatase

 

Yes

N/A

PPM1K

(Oyarzabal et al 2013)

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