Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiency.

3-Hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase EC 4.1.3.4) catalyses the conversion of HMG-CoA to acetyl-CoA and acetoacetate. HMG CoA is formed both 6om leucine catabolism and by the HMG-CoA synthase reaction and plays a vital role in ketogenesis. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency gives rise to 3-hydroxy-3-methylglutaric aciduria and affected patients are unable to synthesise acetoacetate or 3-hydroxybutyrate 6om fat catabolism or protein degradation. They excrete abnormally large amounts of HMG, 3-hydroxyisovalerate (3HV), 3methylglutaconate and 3-methylglutarate in their urine [ 1,2]. Patients appear normal at birth but develop severe acidosis within a few months and 6equently suffer 6om profound hypoglycaemia probably due directly to their inability to synthesise ketone bodies. We have used 'H-n.m.r. spectroscopy to investigate a IZyear old male patient when clinically stable and during an acute catabolic episode d e n 14 samples were collected during a 60 hour period of metabolic decompensation. A fiuther sample was also taken one week later when the patient had stabilised. To 0.5 ml aliquots of urine were added 50 J of DzO containing 20 mM 3-(trimethylsilyl)-2,2,3,3-tetradeuteropropionate (TSP&) for field locking and as an internal chemical shift reference respectively. The samples were run at room temperature in a Jeol GSXSOO spectrometer using a single pulse sequence (30" pulse angle, 2.73 s acquisition time and a 5 s recycling time). Urinary metabolites were quantitated by measuring peak heights relative to the creatinine signals at 3.05 and 4.08 ppm. The patient was admitted to hospital after 48 hours of vomiting with an intercurrent illness. He was semi-comatosed and severely hypoglycaemic. He immediately received dextrose a s i o n s and intravenous Lcarnitine (4g) which has proved beneficial in a number of organic acidurias to assist in the removal of accumulating acyl moieties [2]. Lcarnitine therapy in this disorder leads to increased excretion of acetylcamitine which may be beneficial in reducing the acetyl-CoA pool and releasing fiee CoA. The urinary concentrations of the major abnormal metabolites were elevated above the level seen during clinical stability and he had lactic acidosis (lactate excretion 10.7 moVmol creatinine). Creatine also showed increased excretion as previously observed in this and other patients with organic acidurias during metabolic perturbations