Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without leigh’s disease

Abstract

A child with lactic acidosis, severe mental and developmental retardation, and proximal renal tubular acidosis is presented. Biopsy and autopsy studies show severe hepatic, renal cortical, and cerebral deficiencies in pyruvate carboxylase (EC 6.4.1.1) activity. The patient had 1.81 ± 0.20 units/g fresh weight at biopsy and 0.75 ± 0.07 units/g fresh weight hepatic pyruvate carboxylase activity at autopsy compared with 10.9,11.3, and 9.5 units/g fresh weight in two autopsy and one biopsy controls, respectively. The patient’s renal cortical pyruvate carboxylase activity at autopsy was 0.008 ± 0.004 units/g fresh weight compared with 5.05 units/ g in the autopsy control. The patient had no detectable (<0.018 units/g fresh weight) cerebral pyruvate carboxylase activity at autopsy compared with 0.44,0.53, and 0.695 units/g in the autopsy cerebrum of one. human and two rhesus monkeys, respectively. Pyruvate dehydrogenase complex, phosphoenolpyruvate carboxy- kinase (PEPCK, EC 4.1.1.32), and fructose-1,6-bisphosphatase (EC 3.1.3.11) activities were in the normal range. The patient’s urine pH was above 7.9 when the total serum CO2 was greater than 7.8 mM. However, the patient was able to acidify the urine to pH 5.1 when the total serum CO2 was 1.6 mM. The neuropath- ologic examination of the brain at autopsy revealed no sign of Leigh's disease, although developmental and degenerative lesions were observed. This is the first reported patient with a primary deficiency in hepatic, renal, and cerebral pyruvate carboxylase deficiency in whom the neuropathologic lesions, distinct from those of Leigh’s disease, and proximal renal tubular acidosis have both been documented. Speculation: Application to future patients of methods for the optimal storage and assay of tissues for pyruvate carboxylase activity plus a thorough examination of autopsy brain will demonstrate that the neuropathologic lesions accompanying pyruvate carboxylase deficiency are distinct from those of Leigh's disease. © 1979 International Pediatric Research Foundation, Inc.