Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Mouse model of encephalopathy and novel treatment strategies with substrate competition in glutaric aciduria type I

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 encephalopathy 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 utilization in the immature brain correlates with increased glutaric acid levels and age-dependent susceptibility. 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 promising 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

Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Skvorak et al. [1] demonstrated the therapeutic efficacy of HTx in a murine model of iMSUD, confirming significant metabolic improvement and survival. To determine the effect of HTx on extrahepatic organs, we examined the metabolic effects of HTx in brain from iMSUD animals. Amino acid analysis revealed that HTx corrected increased ornithine, partially corrected depleted glutamine, and revealed a trend toward alloisoleucine correction. For amino acid and monoamine neurotransmitters, decreased GABA was partially corrected with HTx, while the l-histidine dipeptide of GABA, homocarnosine, was decreased in iMSUD mice and hypercorrected following HTx. Elevated branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in MSUD can deplete brain tyrosine and tryptophan (the precursors of monoamine neurotransmitters, dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT)) through competition via the large neutral amino acid transporter. HTx corrected decreased DA levels and the DA metabolite, 3-methoxytyramine, and partially corrected the DA intermediate 3,4-dihydroxyphenylacetate (DOPAC) and 5-HT levels, despite normal tyrosine and tryptophan levels in iMSUD mouse brain. We further observed enhanced intracellular turnover of both DA and 5-HT in iMSUD mouse brain, both of which partially corrected with HTx. Our results suggest new pathomechanisms of neurotransmitter metabolism in this disorder and support the therapeutic relevance of HTx in iMSUD mice, while providing proof-of-principle that HTx has corrective potential in extrahepatic organs