Intracerebral accumulation of glutaric and 3‐hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl‐CoA dehydrogenase deficiency

Abstract

Glutaric acid (GA) and 3-hydroxyglutaric acids (3-OH-GA) are key metabolites in glutaryl co-enzyme A dehydrogenase (GCDH) deficiency and are both considered to be potential neurotoxins. As cerebral concentrations of GA and 3-OH-GA have not yet been studied systematically, we investigated the tissue-specific distribution of these organic acids and glutarylcarnitine in brain, liver, skeletal and heart muscle of Gcdhdeficient mice as well as in hepatic Gcdh -/-mice and in C57Bl/ 6 mice following intraperitoneal loading. Furthermore, we determined the flux of GA and 3-OH-GA across the bloodbrain barrier (BBB) using porcine brain microvessel endothelial cells. Concentrations of GA, 3-OH-GA and glutarylcarnitine were significantly elevated in all tissues of Gcdh -/-mice. Strikingly, cerebral concentrations of GA and 3-OH-GA were unexpectedly high, reaching similar concentrations as those found in liver. In contrast, cerebral concentrations of these organic acids remained low in hepatic Gcdh -/-mice and after intraperitoneal injection of GA and 3-OH-GA. These results suggest limited flux of GA and 3-OH-GA across the BBB, which was supported in cultured porcine brain capillary endothelial cells. In conclusion, we propose that an intracerebral de novo synthesis and subsequent trapping of GA and 3-OH-GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency.

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

“…However, carnitine supplementation at up to 4 times the level given to children during encephalopathic crisis (100 mg/kg every 6 hours) (5) did not provide any improvement in survival. The lack of benefit from carnitine in this model may be related to limited access of dietary supplementation (25,26) or a limited ability to conjugate glutarate in the brain as previously suggested (14).…”

“…Therefore, we considered the possibilities that (a) brain lysine catabolism, which produces glutaric acid, may be reduced with age; (b) brain lysine uptake may be reduced with age; or (c) clearance of glutaric acid from the brain may be enhanced with age. Based on recent findings that showed limited bloodbrain barrier (BBB) permeability for glutaric acid (14), we pursued the first 2 possibilities.…”

Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation

“…Its pathophysiological basis is glutaryl-CoA dehydrogenase deficiency that results in accumulation of organic acids, such as GA and 3OHGA, that share structural and functional similarities with glutamate, in the CNS where they are believed to exert neurotoxic, gliotoxic, and myelinotoxic effects by several pathomechanisms, involving excitotoxic neuronal and oligodendroglial injury, dysregulation of mitochondrial energy production, and oxidative stress (Strauss et al 2003;K€ olker et al 2008. Indeed, in GA-I brain GA has been found to exceed plasma and CSF levels by up to two orders of magnitude even in patients with normal or low GA levels in urine, a counterintuitive finding best explained by the "trapping hypothesis" enunciated by K€ olker et al (Strauss et al 2003;K€ olker et al 2006bMerinero et al 1995;Pineda et al 1998;Nyhan et al 1999;Sauer et al 2006Sauer et al , 2011.…”

“…Leukoencephalopathy, albeit of different etiopathogenesis, extent and clinical characteristics, is an important feature of most cerebral organic acid disorders, including glutaric aciduria type I, aspartoacylase deficiency (or Canavan disease), L-2-hydroxyglutaric aciduria, and D-2-hydroxyglutaric aciduria (K€ olker et al 2006b, 2013Sauer et al 2006Sauer et al , 2011. Notably, macrocephaly is also a frequent and prominent sign of the first three (Strauss et al 2003;K€ olker et al 2011).…”

“…It has been hypothesized that accumulation of organic acids with neurotoxic and myelinotoxic potential might hamper CNS myelination, causing hypomyelination, dysmyelination, delayed myelination, or demyelination, during a critical period of development of the nervous system (K€ olker et al 2006b, 2013Sauer et al 2006Sauer et al , 2011. This is believed to be mediated by several direct or indirect mechanisms affecting immature and mature oligodendrocytes or neurons, such as excitotoxicity via AMPA/kainate and NMDA receptors, impairment of mitochondrial function and oxidative phosphorylation, generation of reactive oxygen species, deregulation of glutamergic and GABAergic neurotransmission, and cytokine-induced amplification of cellular damage (Strauss et al 2003;K€ olker et al 2006b, 2013Sauer et al 2006Sauer et al , 2011Funk et al 2005).…”