Maple Syrup Urine Disease – causes, symptoms, diagnosis, treatment, pathology

Maple Syrup Urine Disease – causes, symptoms, diagnosis, treatment, pathology


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. 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. 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. This molecule is excreted in the urine with
the other metabolic products, which is why the urine has a distinct, sweet odor. 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. This could be triggered by metabolic stressors
like heavy exercise, infections, or fasting, where the body starts to break down its own
proteins. 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.

20 Replies to “Maple Syrup Urine Disease – causes, symptoms, diagnosis, treatment, pathology”

  1. All ur vedios r very much useful in studying medicine but please add some mnemonics too if u can for better and easy learning
    Thank u for making such vedios

  2. I think by taking fenugreek or similar supplements, the side effects can mimic the maple syrup urine symptoms.

  3. The visuals are really creative making the learner remember it in the long run. Thank you so much. It was really valuable and worth watching.

  4. ابني مصاب بهذا المرض وعمره ٢٥ يوم ونسبة الليوسين كانت ١٧٠٠ واثرت على دماغه وذمة دماغية ويبقى نائم في المستشفى وحركاته بطيئة وهم يعطوه حليب msud
    هل تعالج ويعالج من مرضه بحمية غذائية ويعيش حياة طبيعية
    ارجو الرد ارجوكم

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