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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.

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Branched-Chain Ketonuria.

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First described in 1954 by Menkes et al., who lost 4 infants because of neurodegenerative disorder. The urine of these infants had a burned sugar smell. In 1955, Dancis et al., identified the pathogenic compounds as branched chain amino acids and in 1960 confirmed that decarboxylation was responsible.

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Several conditions are described based on the clinical presentation and enzymatic defects for the MSUD.

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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 leucine.

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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.

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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 classic MSUD.

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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 acidosis.

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Thiamine-Responsive Maple Syrup Urine Disease (Thiamine-Responsive MSUD): Thiamine-responsive MSUD is approximately 30 to 40% the normal rate.

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1:120,000 live births. Affects both males and females. All ethnic backgrounds. Increased incidence in the Mennonite (Amish) community in Pennsylvania, USA.

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Autosomal recessive.

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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.

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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 thalami.

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Severity of clinical presentation varies ...

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