A patient with severe neurologic symptoms and acetoacetyl-CoA thiolase deficiency.

A detailed kinetic characterization of the cytosolic acetoacetyl-CoA thiolase in liver, subcutaneous adipose tissue, and cultured fibroblasts of a patient with severe neurologic symptoms showed this enzyme to be much more sensitive to inhibition by CoA than that enzyme of normal human liver. The activity of the cytosolic acetoacetyl-CoA of this patient (14.0 mu mol-min-1-g (w/w) was in the lower range of normal (48.7 +/- 20.4 mu mol-min-1 g (w/w), n=6), but the ratio of the mitochondrial thiolase over the cytosoli thiolase was significantly increased (14.9 versus 4.54 +/- 2.92, n =6). The increased inhibition of the cytosolic acetoacetyl-CoA thiolase by CoA shows up as a 2-fold increase of the apparent Km for acetoacetyl-CoA at physiologic concentrations of CoA (64 micrometer for the enzyme of the patient verus 35 micrometer for the normal enzymes), resulting in a decreased utilization of the substrate. Aberrant kinetic behaviour of the mitochondrial thiolases of the patient has also been observed, but this has not been analysed further. Morphologic studies of the liver showed greatly increased deposition of glycogen and the occurrence of lipofuschin-like granules.