Inherited inborn error of metabolism caused by a
complex enzymatic deficiency of branched-chain α-ketoacid
dehydrogenase leading to the production of urine and sweat that smell like
maple syrup. Clinical features include lethargy, hypotonia, seizures,
bulging fontanelles, and progressive neurologic deterioration. Severe
metabolic acidosis is the cause of death in the newborn.
First described in 1954 by Menkes et al., who lost 4
infants because of neurodegenerative disorder. The urine of these infants
burned sugar smell. In 1955, Dancis et al., identified the pathogenic compounds
chain amino acids and in 1960 confirmed that decarboxylation was
Several conditions are described based on the
clinical presentation and enzymatic defects for the MSUD.
Classic Severe Maple Syrup Urine Disease (Classic Severe MSUD; MSUD Type IA): Characterized by a progressive
infantile cerebral dysfunction defined as lethargy, failure to thrive and
weight loss, severe metabolic derangement, hypotonia and/or hypertonia,
progressive encephalopathy, seizures, and rapidly coma. Affected newborns
appear normal at birth, with symptoms developing between 4 and 7 days of
age. Left untreated, death occurs by age 3 months. This is the most common
form of the disorder, 50% or more of the ketoacids are derived from
Intermediate Maple Syrup Urine Disease (Intermediate MSUD; MSUD Type IB): Characterized by mental retardation,
severe psychomotor delay, mild systemic acidosis, and markedly increased
plasmatic levels of branched-chain amino acids and urinary branched-chain
ketoacids. Other clinical features may include ophthalmoplegia, history of
irritability, poor feeding, and failure to thrive.
Intermittent Maple Syrup Urine Disease (Intermittent MSUD; MSUD Type II): Characterized by episodic ataxia,
lethargy, semicoma, and elevated urinary branched-chain ketoacids. Transient
neurologic disorder can be a mode of presentation. Late onset of symptoms
and clinical normality between attacks differentiate the condition from
E3-Deficient Maple Syrup Urine Disease (MSUD Type III): Combined deficiency of the branched-chain α-ketoacid dehydrogenase pyruvate dehydrogenase and the α-ketoglutarate dehydrogenase complexes. Clinical features include
progressive neurologic deterioration, irregular and difficult respiration,
hypertonia, bilateral optic nerve atrophy, and persistent metabolic
Thiamine-Responsive Maple Syrup Urine Disease (Thiamine-Responsive MSUD): Thiamine-responsive MSUD is approximately 30 to
40% the normal rate.
1:120,000 live births. Affects both males and females.
All ethnic backgrounds. Increased incidence in the Mennonite (Amish) community
in Pennsylvania, USA.
Deficiency of the mitochondrial branched-chain
α-ketoacid dehydrogenase enzyme system, which is responsible for
decarboxylation of the three neutral branched-chain amino acids: leucine,
isoleucine, and valine.
Maple syrup odor of urine. Metabolic acidosis with
elevated ketone bodies and sometimes hypoglycemia. Elevated plasma and urine
levels of leucine, isoleucine, and valine. CT scan shows hypodensity and swelling
of the cerebellar hemispheres, dorsal part of the pons and mesencephalon,
posterior limb of the internal capsule, globus pallidus, and often the
Severity of clinical presentation varies ...