Acute and Chronic‐Intermittent Isovaleric Acidemia: Diagnosis and Glycine Therapy

Abstract

AbstractIsovaleric acidemia is caused by an inherited defect in isovaleryl‐CoA dehydrogenase (E.C. 1.3.99.10). L‐leucine restriction and glycine supplementation are used to decrease the toxic accumulation of isovaleric acid (IVA). Supplemental glycine augments conversion of IVA to isovalerylglycine gVG) through the alternate pathway glycine‐N‐acylase (E.C. 2.3.1.13). Two clinical phenotypes are described, acute and chronic‐intermittent, and are differentiated by enzyme activity in cultured fibroblasts. In this study we determined the optimum therapeutic glycine supplement for treating isovaleric acidemia under stable conditions of restricted leucine intake as compared to oral leucine loading. Under stable clinical conditions and on a restricted leucine intake of 55 mg/kg/day a nine year old with chronic intermittent IVA excreted 12.3 ± 5.8 of IVG which rose to 33.6 ± 14.2 mmoles IVG/gm creatinine as glycine supplements were increased from 0 to 50 mg/kg/day at weekly intervals. Excretion of IVC plateaued between glycine intakes of 50–150 mg/kg, but unexpectedly fell to 13.8 ± 0.5 and 16.3 ± 0.9 mmoles/gm creatinine when glycine supplements were further increased to 300 and 600 mglkglday. IVG excretion increased in a two year old with acute IVA while ingesting 45 mg leucine/kg/day from 5.5 ± 2.8 on no glycine supplement to 10.6 ± 0.8 mmoleslgm creatinine on 600 mg/kg glycine supplements. IVG production was compared in the older patient with chronic intermittent IVA. During acute leucine loads, glycine supplements of 190 or 600 mg/kg/day, resulted in urinary IVG of 194 and 419 mmoles/gm creatinine, respectively.These studies demonstrate that: acute and chronic‐intermittent isovaleric acidemia are differentiated with [1–14C] and [2–14C]‐leucine decarboxylation assays by intact fibroblasts; that glycine supplements of 150 to 250 mg/kg/day are optimum in both forms of the disease when patients are clinically stable but additional supplements will increase IVG production during acute leucine load conditions. However increases in glycine supplementation above 150 mg/kg/day may inhibit IVG production in patients with the chronic intermittent form of isovaleric acidemia, when intracellular IVA accumulation is minimized by diet, or if glycine‐N‐acylase is less competent.