Biochemical Background

The basic biochemical defect in MSUD is a deficiency in branched chain alpha-ketoacid dehydrogenase (BCKDH). This enzyme catalyzes an oxidative decarboxylation of the carbon chain derived from branched chain amino acids (BCAA). The branched chain amino acids metabolized by this enzyme are valine, leucine, and isoleucine.

Normal metabolism of these amino acids would involve first their transamination to the corresponding alpha-ketoacid, followed by oxidative decarboxylation to form the branched-chain carboxylic acids. It is this last reaction that is blocked in MSUD.

According to the crossover theorem of biochemistry, a deficiency in BCKDH activity will result in accumulation of the branched chain amino acids and their corresponding alpha-ketoacid and alpha-hydroxy acids; these compounds appear in blood, urine, and cerebrospinal fluid. The high levels of the alpha-ketoacid and alpha-hydroxy acids are thought to be the proximal cause of neurological damage and mental retardation, but the exact mechanism is not understood.

Overall, the enzyme is quite similar to alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase, and uses the same cofactors. The enzyme has multiple subunits and multiple catalytic activities. The subunits and catalytic activities can be categorized as follows:

E1: 2-oxoisovalerate dehydrogenase, composed itself of two polypeptide chains: E1-alpha (probably the catalytic subunit) and E1-beta; E1 is the most common site of mutations.

E2: dihydrolipoamide acyltransferase.

E3: dihydrolipoamide dehydrogenase.

 

Variants of MSUD

Three variant forms of MSUD have been described so far. Each form is associated with deficient decarboxylation of all three branched-chain ketoacids. There are several variants characterized by various signs and symptoms ranging from life threatening to mild. The most common form of the condition, classic MSUD, is life-threatening in early infancy and requires prompt medical intervention. Symptoms occur within the first week of life after a symptom-free period of 3-4 days.

1. Classic MSUD occurs due to lack of activity of the mitochondrial enzyme complex-branched chain alpha-ketoacid dehydrogenase, the incidence being approximately 1:200,000 infants.

Metabolic Manifestations of classic form: apneas, hypoglycemia, poor feeding, maple syrup odour of the urine and sweat, shrill cry and vomiting. Neurological Manifestations: lethargy leading to coma, hypertonicity, muscle rigidity, boxing and pedaling movements of the limbs, neonatal seizures.

2. Mild intermediate form: decarboxylase activity 5-25% of normal; blood levels of leucine, isoleucine and valine five- to tenfold normal; mental developmental is normal to somewhat retarded. Onset of the disease can be anywhere from infancy to adulthood. It may be accompanied by mild-moderate mental retardation and developmental delays. Episodes precipitated by stress: intercurrent infections, immunization and a sudden increase in dietary protein or surgery. Episodes are characterized by acute ataxia, irritability, maple syrup odour, progressive lethargy, vomiting (excessive).

3. Intermittent form: occurs later in childhood as a consequence of infection or stress; crisis resembles classic MSUD and can be fatal. Similar manifestations occur as for intermediate form.

4. Thiamine-responsive form: decarboxylase activity 20% of normal; blood levels of branched-chain ketoacids threefold normal. Kinetic studies on defective enzyme subunits in classic, intermediate, and intermittent types of disease have shown sigmoidal kinetics with E1-· subunit deficiency, “near-sigmoidal” kinetics with E1-· subunit deficiency, and hyperbolic kinetics with E2 subunit deficiency of BCKDH, respectively. Hyperbolic kinetics or Michaelis-Menten kinetics is described with a rectangular hyperbola relating enzyme velocity to the concentration of substrate. Cooperativity arising between substrate and enzyme, or between enzyme subunits corresponds to sigmoidal kinetics. The difference between the two is that the sigmoidal curve has a “lag phase” corresponding to binding of the first ligand with a lower binding constant, with increasing affinity constants for subsequent ligands (the curve has the shape of letter “S”, which is pronounced “sigma” in Greek).

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