Maple syrup urine disease
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.
The amino acids are then absorbed by the small intestine into the bloodstream, which then travel to the cells of the body, where they are used for protein synthesis.
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.
These intermediates will eventually be converted into acetyl-CoA and succinyl-CoA, which are used by other metabolic processes like the kreb cycle, ketogenesis, or gluconeogenesis.
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.
Once in the brain, they are converted back into leucine, isoleucine, and valine. However, this conversion process uses up other amino acids like aspartate, glutamine, and alanine.
These amino acids are important for brain function and development, especially glutamine, as it is needed to synthesize inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and excitatory neurotransmitter glutamate.
Lack of these two neurotransmitters impairs cell to cell communication. Finally, high levels of alpha- ketoisocaproate inhibit the Krebs cycle, which takes place in the mitochondria.
This process is necessary for the production of ATP, which is used by sodium- potassium pumps to pump sodium out of the cell, and potassium in.
This causes a build up of sodium ions in the cell, which allows water to flow into the cells via osmosis, leading to cellular swelling and cerebral edema.
So where does the maple syrup- smelling urine come from? Well, isoleucine is spontaneously converted into alloisoleucine in the body.
Elevated concentration of plasma alloisoleucine is a sure sign of maple syrup urine disease. Isoleucine and alloisoleucine can also be converted to sotolone, which is the molecule that gives maple syrup and caramel their sweet smell.
Now symptoms differ, based on the form of disease. In classical maple syrup urine disease, the symptoms appear within 48 hours after birth.
These include ketonuria, with the sweet smelling urine, irritability, poor feeding, lethargy or sleepiness, and muscle spasm, called opisthotonos that looks kind of like bicycling movements.
If untreated, in seven to ten days, cerebral edema, seizures, coma, and respiratory failure can occur. In the intermediate form, symptoms appear later in life at irregular intervals.
These symptoms include a maple syrup odor of the urine and also the earwax, feeding problems, and delayed growth and development.
Diagnosis for maple syrup urine disease is based on the presence of clinical symptoms and lab tests that show elevated valine, leucine, isoleucine, and alloisoleucine in the blood, and increased alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV), and alpha-ketoisovalerate (KIV) in urine.
The main treatment consists of strict diet that limits protein consumption. In people with severe symptoms, hemodialysis is sometimes used to remove the excess amino acids.
The only cure is a liver transplantation as the new hepatocytes will have normal levels of BCKD complexes. This procedure is rarely done, and the individual can still pass the mutation onto their children.
All right, as a quick recap, maple syrup urine disease is a rare recessive genetic metabolic disorder where the body cannot break down branched chain amino acids like valine, leucine, and isoleucine, completely due to a deficiency in branched-chain alpha-ketoacid dehydrogenase complexes.
This causes the buildup of these amino acids and their metabolites, which can disrupt brain development, neurotransmitter synthesis, cause cerebral edema, and give the urine a maple syrup odor.
This disorder is diagnosed by elevated plasma levels of valine, leucine, isoleucine, and alloisoleucine in serum, and alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, and alpha-ketoisovalerate in the urine.
Treatment for maple syrup urine disease includes dietary restrictions, hemodialysis, and liver transplant.
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