Isovaleric acidemia: Therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study

Abstract

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. MethodsWe evaluated the patient with IVA beginning at 5years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600mg leucine with glycine alone (250mg/kg/day), l-carnitine alone (100mg/kg/day), or both glycine and l-carnitine for four days each. Results(Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200mg/kg/day) and l-carnitine (100mg/kg/day) supplementation at 5years of age, doses were gradually reduced to 111.7mg/kg/day and 55.8mg/kg/day, respectively, at 15years of age. His mind and body had developed without any sequelae. DiscussionWe concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.