Pyruvate dehydrogenase phosphatase deficiency: a cause of congenital chronic lactic acidosis in infancy
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This study identifies a rare metabolic disorder in a male infant with severe metabolic acidosis. The infant had reduced pyruvate dehydrogenase phosphatase activity, impacting energy metabolism.
Area of Science:
- Biochemistry
- Pediatric Medicine
- Metabolic Disorders
Background:
- Neonatal metabolic acidosis is a critical condition with various causes.
- Pyruvate dehydrogenase complex (PDC) is crucial for carbohydrate metabolism.
- Defects in PDC can lead to severe neurological and metabolic consequences.
Purpose of the Study:
- To investigate the underlying cause of severe metabolic acidosis in a neonate.
- To characterize the enzymatic defect in pyruvate metabolism.
- To understand the implications for energy production in affected tissues.
Main Methods:
- Clinical presentation and biochemical analysis of blood metabolites (lactate, pyruvate, free fatty acids, pH).
- Enzyme activity assays on postmortem tissue homogenates (liver, muscle, brain).
- Investigation of pyruvate dehydrogenase (PDH) activity and its regulation by pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP).
Main Results:
- The patient presented with severe metabolic acidosis, lactic acidosis, and hyperpyruvuvicemia.
- PDH activity was significantly reduced in patient's liver and muscle tissue.
- Enzyme assays revealed a marked deficiency in pyruvate dehydrogenase phosphatase (PDP) activity, leading to impaired PDH function.
- This defect was tissue-specific, affecting liver and muscle but not brain.
Conclusions:
- The patient suffered from a deficiency of pyruvate dehydrogenase phosphatase (PDP).
- This enzymatic defect impairs the activation of the pyruvate dehydrogenase complex, leading to metabolic acidosis.
- The findings highlight the critical role of PDP in energy metabolism and provide insight into a rare cause of neonatal metabolic disease.
Abstract:
A male child presented on the first day of life with metabolic acidosis with elevated blood lactate (15 mM), pyruvate (0.4 mM), and free fatty acid (1.3 mM) levels and a blood pH of 7.16. The severity of the acidosis was diminished by intravenous administration of glucose in large doses and by bicarbonate. On two occasions, when the acidosis was particularly severe, peritoneal dialysis using an acetate buffer was required. Restriction of the dietary intake of saturated fatty acids or treatment with nicotinic acid also appeared to diminish the severity of acidosis. No improvement was achieved by the administration of thiamine or biotin. Tissues taken at postmortem showed normal activity of gluconeogenic enzymes and pyruvate dehydrogenase. The activity of pyruvate dehydrogenase in tissue homogenates preincubated with ATP was reduced by 60-75% both in liver of the patient and of the controls because of the inactivation of the enzyme by pyruvate dehydrogenase kinase. Addition of Ca++ and Mg++ to the inactivated enzyme caused a prompt return of the activity to normal in controls but not in the patient. This defect, which was apparent in muscle and liver but not in brain, we attribute to a markedly reduced activity of pyruvate dehydrogenase phosphatase in the patient.