branched-chain alpha-ketoacid dehydrogenase

**Function and biochemistry** - BCKDH catalyzes the irreversible oxidative decarboxylation of the branched-chain alpha-ketoacids. These come from transamination of leucine, isoleucine, and valine by branched-chain aminotransferase (BCAT), which uses alpha-ketoglutarate as the amino acceptor. - Products: acyl-CoA derivatives (isovaleryl-CoA, alpha-methylbutyryl-CoA, and isobutyryl-CoA), plus CO2 and NADH. - BCKDH is a multi-enzyme complex that closely resembles the pyruvate dehydrogenase complex and the alpha-ketoglutarate dehydrogenase complex. It has three catalytic components: - E1: alpha-ketoacid decarboxylase (E1alpha and E1beta subunits), which requires thiamine pyrophosphate (TPP, from vitamin B1). - E2: dihydrolipoyl transacylase, which requires lipoic acid and CoA (pantothenate, B5). - E3: dihydrolipoyl dehydrogenase, which requires FAD (B2) and NAD+ (B3). - Mnemonic for the cofactors: "Tender Loving Care For Nancy" (TPP, Lipoate, CoA, FAD, NAD+). - Regulation: BCKDH kinase phosphorylates and inactivates the complex. A phosphatase activates it. Branched-chain ketoacids, especially the leucine-derived alpha-ketoisocaproate, inhibit the kinase. - Fates after the acyl-CoA step: - Leucine is purely ketogenic. It yields acetyl-CoA and acetoacetate. - Isoleucine is both ketogenic and glucogenic. It yields acetyl-CoA and succinyl-CoA (via propionyl-CoA). - Valine is purely glucogenic. It yields succinyl-CoA. - Branched-chain amino acids are essential amino acids. They are also metabolized mostly in skeletal muscle, which has high BCAT activity. The liver has high BCKDH activity.

**Pathophysiology of deficiency: maple syrup urine disease (MSUD)** - Inheritance is autosomal recessive. Mutations occur in the BCKDHA (E1alpha), BCKDHB (E1beta), DBT (E2), or DLD (E3) genes. - Branched-chain amino acids and their ketoacids accumulate in blood, urine, and CSF. - Leucine and its ketoacid alpha-ketoisocaproate are the main neurotoxins. They cause cerebral edema and disrupt neurotransmitter synthesis. They also impair brain amino acid transport, because leucine competes with other large neutral amino acids at the LAT1 transporter. - Isoleucine metabolites (sotolone) give the urine, sweat, and cerumen the odor of maple syrup or burnt sugar.

**Clinical features** - Presentation is in the first days to weeks of life, after a period of normal feeding. - Early signs: poor feeding, vomiting, lethargy, irritability, and a sweet odor in the urine and cerumen. - Later signs: hypertonia alternating with hypotonia, opisthotonus, "bicycling" movements, seizures, encephalopathy, and coma. Cerebral edema can lead to death. - Metabolic crises can be triggered by infection, fasting, surgery, or other catabolic stress. These cause protein breakdown and release of branched-chain amino acids from muscle. - Milder variants (intermediate, intermittent, and thiamine-responsive forms) present later and have residual enzyme activity.

**Diagnosis** - Plasma amino acids: elevated leucine, isoleucine, and valine, with alloisoleucine as a pathognomonic marker. - Urine organic acids: branched-chain ketoacids. - Newborn screening by tandem mass spectrometry. - The 2,4-dinitrophenylhydrazine (DNPH) urine test is positive but is historical.

**Treatment** - Lifelong dietary restriction of leucine, isoleucine, and valine, using a special formula. Some branched-chain amino acids must still be supplied because they are essential. - Thiamine supplementation, because some patients respond. - Acute crisis: stop protein intake, give high-calorie IV glucose and insulin to promote anabolism, and give isoleucine and valine supplements to compete with leucine. Hemodialysis or hemofiltration may be needed for severe leucine toxicity. - Liver transplant can be curative because it provides enzyme activity.

**Board-style pearls** - A neonate with poor feeding, lethargy, and sweet-smelling urine has MSUD until proven otherwise. - Defect: decreased alpha-ketoacid dehydrogenase, with increased branched-chain amino acids and their alpha-ketoacids in the blood. - It is a mitochondrial matrix enzyme complex that needs five cofactors. Related complexes that use the same cofactors are pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. - Compare with other conditions: - Pyruvate dehydrogenase deficiency: lactic acidosis and neurologic defects, treated with a ketogenic diet (lysine and leucine are the purely ketogenic amino acids). - Isovaleric acidemia: "sweaty feet" odor. It is a defect in isovaleryl-CoA dehydrogenase, which acts after BCKDH in leucine metabolism. - Phenylketonuria: musty or mousy odor. - Homocystinuria: marfanoid habitus and lens dislocation (downward). - Alkaptonuria: dark urine and ochronosis.