Chapter 58: Biochemical Case Histories

The first case investigates a growth-retarded child with elevated immunoreactive insulin but low biological activity, suggesting a defect in the proteolytic processing of proinsulin into active insulin and C-peptide. The second case illustrates the metabolic consequences of chronic alcoholism and malnutrition, specifically thiamine deficiency leading to severe lactic acidosis, high-output cardiac failure (wet beriberi), and disruptions in pyruvate metabolism. The text contrasts two distinct forms of hemolytic anemia linked to the pentose phosphate pathway: one induced by oxidative drugs like primaquine in a patient with an unstable Glucose-6-Phosphate Dehydrogenase (G6PD) variant, and another triggered by fava beans (favism) in a patient whose G6PD enzyme exhibits an abnormally high Km for NADP+. These cases highlight the importance of NADPH and reduced glutathione in protecting erythrocytes from oxidative damage. Further cases explore organic acidemias, such as propionic acidemia characterized by hyperammonemia and accumulation of propionyl-CoA metabolites like methylcitrate, confirming a blockade in the conversion of propionate to succinyl-CoA. The chapter also details HMG-CoA lyase deficiency, where a defect in leucine catabolism and ketogenesis causes non-ketotic hypoglycemia and a distinctive urine odor described as cat-like. Another metabolic error involves biotin metabolism, where a child presenting with alopecia, dermatitis, and organic aciduria responds to high-dose biotin therapy, indicative of a multiple carboxylase deficiency likely affecting biotinidase or holocarboxylase activity. Mitochondrial dysfunction is examined through a case of lactic acidosis and developmental regression caused by pyruvate carboxylase deficiency, which impairs gluconeogenesis and anaplerotic flux into the TCA cycle. The final case differentiates Maturity-Onset Diabetes of the Young (MODY) from Type 1 and Type 2 diabetes, focusing on glucokinase mutations that alter the glucose-sensing mechanism of pancreatic beta cells and the subsequent regulation of insulin secretion. Collectively, these histories demonstrate the clinical utility of measuring specific metabolites, such as plasma ammonium, lactate, and organic acids, to diagnose inborn errors of metabolism.