Introduction to Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is
a genetic metabolic disorder of branched chain amino acids (BCAA) catabolism (Levy, et al., 2013). This causes
deficiency in BCKD resulting in a metabolic error (Strauss, et al., 2006).

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The symptoms include maple syrup
odour of urine and ear wax, poor feeding, nausea, vomiting, irritability, lethargy,
seizures, and ataxia (Levy, et al., 2013). It can lead to encephalopathy, coma,
mental disorders and death (Strauss, et al., 2006).

Blood test will reveal increased
plasma concentration of BCAA, especially leucine (Strauss, et
al., 2006).
Urine testing can identify ketonuria and other organic acids (Levy, et al., 2013). Genetic testing to reveal mutations is
also performed (Strauss, et al., 2006).

The first step in intervention will
be to discontinue all protein intake (Levy, et al., 2013). Haemodialysis can be useful in
managing brain oedema (Strauss, et al., 2006). Another possible
therapy is also a liver transplant (Burrage, et al., 2014).


BCAA Catabolism and MSUD

BCAAs are leucine, isoleucine and
valine (Figure 1.) and they classify as essential amino acids (Cole, 2015). Valine is purely
glucogenic, leucine is ketogenic and isoleucine has both ketogenic and
glucogenic nature (Brosnan & Brosnan, 2006). Out of total amino
acid requirement of the body, BCAAs represent approximately 35% (Brosnan & Brosnan, 2006).



The BCAA catabolism is unique as
the primary catabolic steps proceed in skeletal muscle mitochondria not in the
liver (Brosnan & Brosnan, 2006) and the first two
steps share enzymes (Burrage, et al., 2014). The first step
(Figure 2.) is a transamination reaction catalysed by branched chain
aminotransferase (BCAT) (Burrage, et al., 2014). There are two forms
of BCAT, cytosolic and mitochondrial (Cole, 2015).
During transamination, ?-oxoglutarate accepts the ?-amino group from the
specific BCAA and will form glutamate, the BCAA will form their derivative
branched chain keto acid (BCKA) (Cole, 2015).
The cofactor for this reaction is vitamin B6 (Cole, 2015).

The second step (Figure 3.) is rate
regulating and irreversible (Cole, 2015)
oxidative decarboxylation of BCKA (Burrage, et al., 2014). The enzyme in this
reaction is BCKD complex requiring these cofactors: thiamine pyrophosphate
(vitamin B1), coenzyme A, Flavin and nicotinamide adenine dinucleotides (FAD
and NAD) and lipoamide (Burrage, et al., 2014). After the second
step, each BCAA will follow different pathway (Figure 4.) according to their
glucogenic or ketogenic nature (Cole, 2015).


In MSUD, the deficiency of BCKD
prevents the second step from proceeding (Cole, 2015)
(Figure 5.), therefore the BCAAs and their derivative BCKAs will accumulate in
the plasma causing the previously mentioned symptoms. Their neurotoxicity
mechanism is to be yet completely understood, however leucine is the most
neurotoxic (Burrage, et al., 2014). It is possible that
leucine prevents the precursors of neurotransmitters from transporting across
the blood-brain barrier and also disturbing the energy metabolism in the brain (Burrage, et al., 2014). The accumulation of
BCKAs in plasma can lead to metabolic acidosis which can be fatal (Levy, et al., 2013).



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