Mouse model of encephalopathy and novel treatment strategies with substrate competition in glutaric aciduria type I William J. Zinnanti a, * , Jelena Lazovic b a Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA b Department of Biology, California Institute of Technology, Pasadena, CA, USA article info Article history: Received 25 January 2010 Accepted 22 February 2010 Available online 1 March 2010 Keywords: Glutaric aciduria Metabolic encephalopathy Mouse model abstract Glutaric aciduria type I (GA-1) results from an inherited defect in a common step of lysine, hydroxylysine and tryptophan metabolism. This defect is associated with an age-dependent susceptibility to encepha- lopathy commonly preceded by non-specific childhood illnesses or fasting. The brain injury that develops with encephalopathic crisis in GA-1 is anatomically and symptomatically similar to Huntington’s disease, affecting the striatum. The mechanism of injury remains poorly understood. Recently, an animal model of GA-1 encephalopathy was developed by providing GA-1 mice with added dietary lysine. This model shows age-dependent susceptibility similar to the human disease. Enhanced lysine accumulation and uti- lization in the immature brain correlates with increased glutaric acid levels and age-dependent suscep- tibility. Neurotransmitter and Krebs cycle intermediate depletion in this model represent novel findings toward uncovering the mechanism of neuronal injury. Additionally this mouse model is responsive to glucose analogous to human GA-1 and provides insight toward the mechanism of this effect. Together these findings led to a new treatment strategy of competing with brain lysine uptake that shows prom- ising results. This research serves as a model for understanding blood brain barrier amino acid transport at critical stages of development and may help advance understanding of brain injury and development of treatments in other IEMs including urea cycle disorders. Ó 2010 Published by Elsevier Inc. Introduction Deficiency of glutaryl-conenzyme A dehydrogenase (EC 1.3.99.7) (GCDH) disrupts the normal breakdown of lysine, hydroxyline and tryptophan, causing glutaric aciduria type I (GA- 1). Autosomal recessive inheritance of GCDH deficiency is one of the more common inherited metabolic disorders affecting 1:30,000–1:100,000 children worldwide [1,2]. The disrupted bio- chemical pathway in GA-1 involves a common step in the break- down of essential amino acids:lysine and tryptophan. Lysine and tryptophan are transported into cells and across the blood–brain barrier via the cationic amino acid transporter 1 (CAT-1) and the large-neutral amino acid transporter (LAT1), respectively [3]. The LAT is common to the substrates in other inborn errors of metab- olism such as phenylketonuria and urea cycle disorders (UCD). Once inside the cell, lysine may be taken up and broken down in mitochondria directly via the ornithine carrier (ORC1) [4]. On the other hand, tryptophan has other metabolic pathways in which to participate including kynurenine, quinolinate, serotonin and melatonin pathways [5]. Through the kynurenine pathway, trypto- phan is oxidized to alpha-ketoadipate, which is then taken up into the mitochondria. Alpha-ketoadipate is further oxidized to gluta- rate and conjugated to coenzyme A to form glutaryl-CoA. GCDH is required for further oxidation to crotonyl-CoAand then to aceto- acetyl-CoA that can enter the Krebs cycle as acetyl-CoA. In GCDH deficiency, glutaryl-CoA, glutaryl-carnitine, free glutaric and 3- hydroxyglutaric acid accumulate. Children with GA-1 typically have enlarged head circumference at birth and accumulation of glutaric acid and glutaryl-carnitine that may be detected in blood or urine. It is not clear if head enlargement is secondary to chronically elevated cerebrospinal fluid pressure, since both elevated and normal pressures have been found in these patients [6]. After a period of normal development, if left untreated, children with GA-1 usually experience encephalo- pathic crisis in the context of non-specific illness between 6 and 18 months of age. Encephalopathic crisis in GA-1 results in bilat- eral striatal damage with devastating consequences [7,8]. Affected individuals accumulate substantial glutaric acid in the brain and 3- hydroxyglutaric acid (3-OHGA) to a lesser extent [9–11]. The neu- ropathology associated with GA-1 is similar to that of Huntington’s disease, showing specific striatal degeneration involving loss of medium spiny neurons and astrogliosis [9–13]. Unlike the chronic 1096-7192/$ - see front matter Ó 2010 Published by Elsevier Inc. doi:10.1016/j.ymgme.2010.02.022 * Corresponding author. Address: Department of Pediatrics, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. E-mail address: wzinnanti@gmail.com (W.J. Zinnanti). Molecular Genetics and Metabolism 100 (2010) S88–S91 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme