Practical management of organic acidemias

Abstract

Organic acidemias or acidurias (OAs) are a group of metabolic disorders which result in organic acids detected in the urine (or plasma). They include the systemic OAs, the cerebral OAs, and the ketogenic/ketolytic OAs. In general, all types of OA can be treated using a similar conceptual organization. The goals of therapy (acute and chronic) include reversal/prevention of catabolism, limitation of non-tolerated precursors, scavenging of toxic intermediates, replacement of the deficient product, use of cofactors when able and treatment of complications using standard methods. In the future, this framework will also include replacement of dysfunctional enzyme with a functional one. Here we review how this conceptional framework applies to the systemic OAs (propionic acidemia, methylmalonic aciduria without homocystinuria, and isovaleric acidemia), the cerebral OA (glutaric aciduria 1) and the ketogenic/ketolytic OA (HMG-CoA lyase deficiency). We review the current recommendations and use examples of how to use this conceptional framework.

Cardiac Complications of Propionic and Other Inherited Organic Acidemias

“… Whilst cardiac dysfunction has been reported in both of the commonest OAs, PA and MMA, cardiac disease only occurs commonly in PA. Collated information from the U.S. NIH National Library of Medicine Genetics Home Reference, Schwartz et al ( 27 ), Chapman ( 3 ), and cited reports as per main text . HF, heart failure; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LVH, left-ventricular hypertrophy; LVNC, left-ventricular non-compaction cardiomyopathy; OA, organic acidemia/aciduria; OMIM, Online Mendelian Inheritance in Man; TdP, torsades de pointes; VT, ventricular tachycardia; VF, ventricular fibrillation .…”

“…Whilst cardiac dysfunction has been reported in both of the commonest OAs, PA and MMA, cardiac disease only occurs commonly in PA. Collated information from the U.S. NIH National Library of Medicine Genetics Home Reference, Schwartz et al ( 27 ), Chapman ( 3 ), and cited reports as per main text .…”

“…Mevalonic aciduria is considered a cerebral organic acidemia ( 3 ). It results from a deficiency in mevalonate kinase (involved in the early steps of cholesterol biosynthesis), however a defect in mevalonate kinase can also result in hyperimmunoglobulinemia D syndrome.…”

“…Organic acidemias (OAs), sometimes referred to as organic acidurias, are a subset of 17 IMDs that are characterized by the excessive accumulation of organic acids in body fluids. OAs have been divided into three categories: (1) systemic, (2) cerebral, and (3) ketolytic/ketogenic ( 3 ), although this naming system is problematic because changes related to the brain are common in all OAs and the canonical cerebral OAs can also develop non-neurologic manifestations ( 4 ). With the advent of chemical assays capable of defining the metabolite milieu of blood, OAs have been related to specific metabolic signatures, some of which have diagnostic value.…”

“…A feature of many OAs is the accumulation of organic acid metabolites that directly relate to the mutated enzyme, typically accompanied by a build-up of various other acidic metabolites particularly during stages of metabolic decompensation, such as lactate, 3-hydroxybutyrate or acetoacetate. The clinical management of OAs is broadly based on the same principles, namely, the reversal or prevention of catabolism, limiting exposure to precursors of the substrate that cannot be metabolized, and scavenging toxic intermediates ( 3 ).…”