AssessmentsMaple syrup urine disease
Maple syrup urine disease
USMLE® Step 1 style questions USMLE
A 2-month-old infant comes to the clinic because of progressive weakness and increased sleep over the past 4 weeks. This is his mother’s first-born son. She was in Mexico during delivery and says that she had a regular 39 weeks’ gestation. She took folic acid during her pregnancy. The infant was born through vaginal delivery with no complications. Apgar scores were 10 and 9 at 1 and 5 minutes, respectively. The neonate did not go through a newborn screening process. His temperature is 37.2°C (98.96°F), pulse is 130/min and respirations are 43/min. Physical examination shows lethargy, hypotonia and weak response to primitive reflexes. There is a “honey-like” odor around his diaper which the mother says has been present since birth. Which of the following enzymes is most likely deficient in this patient?
Content Reviewers:Yifan Xiao, MD
Maple syrup urine disease is a rare genetic metabolic disorder where the body cannot break down branched chain amino acids like valine, leucine, and isoleucine completely, causing buildup of these amino acids and their toxic metabolic byproducts.
It was named maple syrup urine disease since the urine that contain these metabolites smell like maple syrup.
Other names for this disease include branched- chain ketoacid dehydrogenase deficiency, or BCKD deficiency, and branched- chain ketoaciduria.
Now, amino acids are the basic building blocks that make up proteins.
There are 20 amino acids used in the human body and they all contain a carboxyl group (-COOH) and an amine (-NH2) group.
The branched chain amino acids have a side chain containing 3 or more carbons, and they include valine, leucine, and isoleucine.
These 3 are essential amino acids, meaning our bodies can’t create them, so they must be acquired through protein rich foods like meat, eggs, dairy, avocados, beans, etc.
So the proteins you eat are broken down into amino acids in the gastrointestinal tract by gastric acid and digestive enzymes.
Since the body can’t store these amino acids, any extra amino acids are converted into glucose or ketones and used for energy.
Branched chain amino acids: valine, leucine and isoleucine, require special steps during their catabolism.
First, the enzyme branched- chain amino transferase, or BCAT, strip off their alpha amino group and transfers it to an alpha ketoglutarate to form glutamate.
This also converts the branched- chain amino acids into branched- chain keto acids.
Valine into alpha-ketoisovalerate, or KIV, leucine is converted into alpha-ketoisocaproate, or KIC, and isoleucine into alpha-keto-beta-methylvalerate, or KMV.
In the second step, branched-chain alpha-keto acid dehydrogenase complex, or BCKD, removes the carboxyl group from these keto acids and turns them into the intermediates isobutyryl-CoA, isovaleryl-CoA, and alpha-methylbutyryl-CoA respectively.
Maple syrup urine disease is an autosomal recessive disorder, where there’s a mutation in at least one of the four genes that codes for the BCKD complex.
The more common form of this disease is called the classical form, and it’s where there’s little to no functional complexes.
The less severe form is called the intermediate form, where only 5-8% of the complexes are functional, when compared to normal.
Decreased BCKD complex activity means that all the branched chain amino acids and their first step metabolites such as alpha- ketoisovalerate, alpha- ketoisocaproate, and alpha- keto- beta- methylvalerate build up in the blood and body tissues like the brain, muscle, and liver.
Now, there’s a highly selective barrier between the brain tissue and blood vessels called the blood- brain barrier.
This blood- brain barrier has amino acid transporters that allow a limited amount of amino acids to cross from the blood into the brain.
Leucine binds with higher affinity to these transporters than other amino acids, so they end up occupying most of the transporters.
This limits the amount of other amino acids that can enter the brain.
Some of these, like tyrosine, tryptophan, and threonine are used for the synthesis of neurotransmitters like dopamine and serotonin.
Now let’s zoom into the blood brain barrier.
Some of the metabolites of branch chain amino acids can also cross over from the blood into the brain.