Maple Syrup Urine Disease

MAPLE SYRUP URINE DISEASE
background
• Maple syrup urine disease (MSUD), also known as branched-chain ketoaciduria, is an
aminoacidopathy due to an enzyme defect in the catabolic pathway of the branched-chain amino
acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding
alpha-keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants.
Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual
development
• In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of life owing
to a neurodegenerative disorder. The urine of these infants had an odor similar to that of maple
syrup (burnt sugar). Therefore, this disorder was called maple sugar urine disease and, later, maple
syrup urine disease. In the following years, Dancis et al identified the pathogenetic compounds as
branched-chain amino acids and their corresponding alpha-keto acids.
• It is important to remember that an out-of-range screening result does not necessarily mean
that your child has the condition. An out-of-range result may occur because the initial blood
sample was too small or the test was performed too early. However, as a few babies do have the
condition, it is very important that you go to your follow-up appointment for a confirmatory test.
Because the harmful effects of untreated MSUD can occur soon after birth, follow-up testing must
be completed as soon as possible to determine whether or not your baby has the condition.
Babies with classic MSUD usually begin showing signs shortly after birth. These signs include:
• Poor appetite
• Trouble sucking during feeding
• Weight loss
• High pitched cry
• Urine that smells sweet like maple syrup or burnt sugar
• Sleeping longer or more oftenTiredness
• Irritability
• Vomiting
• Developmental delays
CAUSES
• MSUD is caused by changes (mutations) in three different genes:
BCKDHA, BCKDHB and DBT. Mutations in these genes result in
absent or decreased activity of human branched-chain alpha-ketoacid
dehydrogenase complex (BCKAD) enzymes. These enzymes are
responsible for breaking down the branched chain amino acids leucine,
isoleucine, and valine that are in protein-rich foods, [The BCAAs are the
only amino acids that have a split main carbon chain]. Accumulation of
these amino acids and their toxic byproducts (ketoacids) results in the
serious health problems associated with MSUD. The toxicity of these
amino acids seems to be restricted to the leucine; indeed, extra valine
and isoleucine are often given during treatment. Accumulation of their
respective ketoacids results in metabolic acidosis
DIAGNOSIS
• Many infants with MSUD are identified through newborn screening
programs. Tandem mass spectrometry, an advanced newborn
screening test that screens for more than 30 different disorders through
one blood sample, has aided in the diagnosis of MSUD. Infants with
mild or intermittent forms of the disorder may have totally normal blood
amino acids after birth and thus can be missed by newborn
screening.In places where testing for MSUD is unavailable or where
newborn screening fails to detect MSUD, a diagnosis may be
suspected based upon symptomatic findings (lethargy, failure to thrive,
neurologic signs or, during a metabolic crisis, odor of maple syrup in
earwax, sweat or urine). Tests to diagnose MSUD may include urine
analysis to detect high levels of keto acids (ketoaciduria) and blood
analysis to detect abnormally high levels of amino acids
STANDARD THERAPIES
• The treatment of classic, intermediate, intermittent, and thiamine-responsive
MSUD has two chief components: lifelong therapy to maintain acceptable amino
acid levels in the body and immediate medical intervention for metabolic
crises.Individuals with MSUD must remain on a protein-restrictive diet that limits
the amount of branched-chain amino acids they take in. Protein-restriction must
start as soon as possible after birth to promote proper growth and development.
Artificially-made (synthetic) formulas are available that provide all the nutrients
necessary for proper growth and development, but lack leucine, isoleucine and
valine. It is particularly important to limit the amount of leucine in the diet. The
three amino acids are added to the diet separately in small amounts so that
affected individuals can grow and develop normally. The amount of leucine,
isoleucine and valine that can be tolerated by a child varies based upon residual
enzyme activity. Affected children must be regularly monitored to ensure that their
amino acid levels remain within acceptable normal ranges.

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MAPLE SYRUP URINE DISEASE

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