Glutaric Acidemia, Pathogenesis and Nutritional Therapy

Abstract

Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. The disorders can be divided into type I and type II by the occurrence of different types of recessive mutations of autosomal, metabolically important genes. Patients of glutaric acidemia type I (GA-I) if not diagnosed very early in infanthood, experience irreversible neurological injury during an encephalopathic crisis in childhood. If diagnosed early the disorder can be treated successfully with a combined metabolic treatment course that includes early catabolic emergency treatment and long-term maintenance nutrition therapy. Glutaric acidemia type II (GA- II) patients can present clinically with hepatomegaly, non-ketotic hypoglycemia, metabolic acidosis, hypotonia, and in neonatal onset cardiomyopathy. Furthermore, it features adult-onset muscle-related symptoms, including weakness, fatigue, and myalgia. An early diagnosis is crucial, as both types can be managed by simple nutraceutical supplementation. This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. We will provide a detailed summary of current clinical management strategies of the glutaric academia disorders and highlight issues of nutrition therapy principles in emergency settings and outline some specific cases.

Keywords: Glutaric acidemia; genetic disorders; maintenance therapy; nutrition therapy; pathogenesis.

Figure 1

Disorders of lysine and tryptophan metabolism in GA-I. Lysine and tryptophan enter cells through distinct sodium-independent facilitative amino acid transporters. These amino acids are converted to ketoadipic acid (KA) in the cytosol through glutamate/ketoglutarate-coupled transamination and transported into mitochondria. Subsequently, KA is oxidatively decarboxylated under the catalysis of α-ketoglutarate dehydrogenase (KGDH). It utilizes free CoA to form glutaryl-CoA, which can undergo conjugation with carnitine to form C5DC. Glutaryl-CoA dehydrogenase catalyzes the conversion of glutaryl-CoA to crotonyl-CoA in a two-step reaction, first dehydrogenated to glutaconyl-CoA, and second decarboxylated to crotonyl-CoA. A mutated GCDH enzyme cannot metabolize glutaryl-CoA to crotonyl-CoA resulting in accumulation of GA, glutaryl-CoA and 3-OH-GA, which have been proposed to act as endogenous neurotoxins.

Figure 2

Catabolic pathways of the Lysine metabolism. Competition between L-arginine and L-lysine at the mitochondrial membrane and the blood-brain barrier. Catabolic pathways: (1) the mitochondrial saccharopine pathway is the major route in liver; (2) the peroxisomal pipecolate pathway is the major route in brain, both branches converge in α-AASA and its cyclic equivalent P6C. Acetyl-CoA is the ultimate product of the lysine degradation. human mitochondrial ornithine carriers 1 and 2 (ORC); system y+ of the blood–brain barrier (y+), pipecolate oxidase (PIPOX), AASS, α-aminoadipate semialdehyde synthase (AASS); piperideine-6-carboxylate (P6C);α-aminoadipate semialdehyde (α-AASA); α-AAA, α-aminoadipate (α-AAA); tricarboxylic acid-cycle (TCA cycle).

Figure 3

Metabolic disorders of fatty acid in GA-II. Mutations in the Electron Transfer Flavoprotein (ETFA, ETFB) or Electron Transfer Flavoprotein Dehydrogenase (ETFDH) genes. These genes encode the α/β subunits of Electron Transfer Flavoprotein (ETF) and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase (ETF-QO) respectively. ETF and ETF-QO are the key transporters in the process of electron transfer of fatty acid β-oxidation. In mitochondria, ETF, which is located in the matrix, receives electrons from several FAD-containing acyl-CoA dehydrogenases involved in fatty acid oxidation. ETF transfers electrons to ETF-QO, located in the inner mitochondrial membrane and, subsequently, electrons are passed to ubiquinone in the respiratory chain. Consequently, a dysfunction of ETF or ETF-QO causes the final process of fatty acid β-oxidation to fail, thereby leading to disturbed ATP biosynthesis from fatty acid, excessive lipid accumulation and disturbed gluconeogenesis, Complex I (NADH: ubiquinone reductase), complex II (succinate: ubiquinone reductase), complex III (ubiquinol: cytochrome C oxidoreductase or cytochrome bc1 complex), complex IV (cytochrome c oxidase).

Figure 4

Electron transfer system in the respiratory chain. Riboflavin is converted to FAD, as cofactor for both ETF and ETFDH, also enter as a coenzyme for complex I and II in the respiratory chain.

Figure 5

Carnitine Shuttling System. Once the free fatty acid reaches the Mitochondrium, it is processed into a fatty acid acyl CoA molecule by Fatty Acyl-Coenzyme A Synthetase (FACS) to cross the outer mitochondrial membrane. Carnitine is used by Carnitine Palmitoyl transferase 1 (CPT1) to synthesize acyl carnitine, which is shuttled across the inner mitochondrial membrane by Carnitine Translocase (CACT). Finally, acyl carnitine is converted back into carnitine, and a fatty acid acyl-CoA molecule by carnitine palmitoyl transferase 2 (CPT2) for β-oxidation within the mitochondrial matrix, and transport of free carnitine back to the cytoplasm by CACT.