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ERRORS OF PROTEIN METABOLISM THAT INVOLVE THE LEUCINE PATHWAY

The errors of protein metabolism that involve the leucine pathway are: (1) maple syrup urine disease (MSUD), (2) dihydrolipoyl dehydrogenase deficiency, (3) isovaleric acidemia, (4) glutaric acidemia type II, (5) multiple carboxylase deficiency, and (6) hydroxymethylglutarate-CoA lyase deficiency.

Branched chain beta-keto acid dehydrogenase deficiency

A block in the metabolism of leucine due to branched chain beta-keto acid dehydrogenase deficiency occurs in MSUD and in dihydrolipoyl dehydrogenase deficiency (Figure 72.1 A, B).

Figure 72.1.— Leucine pathway showing different enzymatic blocks and the amino acids that increase as a result of the block. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

Maple syrup urine disease
Maple syrup urine disease combines a block in leucine metabolism with blocks in the metabolism of isoleucine and valine (Figure 72.2 A).

Figure 72.2.— Metabolic pathways involved in branched chain amino acid disorders. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

Three findings may suggest MSUD prior to the serum amino acid result: (1) a burnt sugar smell in the urine; (2) an interictal EEG with runs of 5 to 7 Hz monophasic, central, or parasagittal negative activity during awake or sleep; or (3) a brain imaging study showing dorsal brainstem edema (Figure 72.3).

A
B

Figure 72.3.— MRI demonstrating brainstem edema in a neonate with maple syrup urine disease.

 
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HMG-CoA lyase deficiency multiple carboxylase deficiency glutaric acidemia type II isovaleric acidemia dihydrolipoyl dehydrogenase deficiency maple syrup urine disease branch chain alpha-keto acids produces alanine and lactate becomes alanine and lactate citric acid cycle rate-limiting enzyme deficiency produces energy failure elevation of alloisoleucine HMG-CoA lyase deficiency multiple carboxylase deficiency isovaleric acidemia glutaric acidemia type II dihydrolipoyl dehydrogenase deficiency maple syrup urine disease thalamus tectum cerebellum brainstem edema sylvian fissure sylvian fissure vermis brainstem edema extending to the diencephalum Instructions Instructions Tharp, 1992 Click on figure for animated labels. Pause pointer on different areas of the figure for labels. Figure must be centered. Pause pointer over each bar or letter. Figure must be centered. Pause pointer over each bar or letter. Figure must be centered.