Question

10. A 6-month old girl presents with the following symptoms: lactate acidosis (elevated serum levels of lactate), elevated levels of alanine in both her urine and blood, and muscle weakness (suggesting low levels of ATP). Doctors diagnose her problem as dihydrolipoamide dehydrogenase deficiency (present in two complexes!). They attempt to treat the girl with dietary supplements of riboflavin, thiamine, and niacin. a) Explain how this enzyme deficiency gives rise to lactate acidosis. (What's backing up, and where is it going?) (3 pts) b) Explain how this enzyme deficiency gives rise to elevated levels of alanine in her urine and blood. (2 pts) c) Choose one of the three dietary supplements: riboflavin, thiamine, or niacin. Briefly explain how it might help this girl's condition. Cite the enzyme(s) that benefit from the treatment in each case. (3 pts)

Answer 1

A) Dihydrolipoamide dehydrogenase(DLD) is a component of 3 different group of enzymes, Branched chain alpha keto acid dehydrogenase(BCKD), pyruvate dehydrogenase(PDH) and alpha- ketoglutarate dehydrogenase . In DLD deficiency disease is because of mutation in DLD enzyme. Improper functioning of DLD enzyme prevents the proper functioning of the three enzyme complexes.

BCKD is involved in breakdown of aminoacids like leucine, isoleucine and valine. PDH deficiency leads to build up of pyruvate in the body. It gets converted into lactic acid. Build up of lactic acid leads to acidosis.

B) PDH complex converts pyruvate into acetyl CoA. In DLD deficiency, this complex doesn't work so Acetyl CoA is not formed. Therefore, citric acid cycle does not work which requires Acetyl CoA for its function. Citric Acid cycle utilises many aminoacids like alanine which are increased in levels in DLD deficiency.

C)Thiamine pyrophosphate (TPP) is a cofactor of BCKD enzyme complex. Thiamine supplementation leads to increased tolerance to branched chain aminoacids (BCAA) and maintains their levels in the body. This will improve the girl's condition.

Riboflavin supplements- PDH and BCKD enzyme complexes require riboflavin as a cofactor.

Niacin supplements- PDH requires Niacin as a cofactor.

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