Pathomechanisms of neurodegeneration in glutaryl‐CoA dehydrogenase deficiency

Abstract

Glutaryl-CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3-Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3-Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. Furthermore, glutaric and 3-hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3-hydroxyglutaric and glutaric acid toxicity.

Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias

“…An additional increase in plasma and brain concentrations of these metabolites during catabolic crises is thought to be responsible for acute striatal degeneration. Prerequesite for the cytotoxic effects of GA and 3OHGA on brain and vascular cells [4,21] is the transport of metabolites across various biological membranes, including mitochondrial and plasma membranes and trans-endothelial transport.…”

“…Glutaric aciduria type 1 (GA1) is caused by deficiency of glutaryl-CoA dehydrogenase (EC 1.3.99.7; GCDH), a mitochondrial enzyme involved in the degradation of tryptophan and lysine. Defective GCDH causes insufficient glutaryl-CoA breakdown and results in an accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), glutaconate (GC), and glutarylcarnitine in tissues, plasma, cerebrospinal fluid, and urine [1][2][3][4]. During catabolic situations, GA1 patients are subject to the development of encephalopathic crises, leading to striatal degeneration with a subsequent irreversible dystonic-dyskinetic movement disorder.…”

“…Histopathological findings include neuronal loss and astrogliosis in the striatum, subdural hemorrhages, and spongiform vacuolation of the white matter. These symptoms and the associated histopathological changes in putamen and caudatum mainly occur between the 3rd and 36th month of age triggered by a nonspecific disease like fever, respiratory infection, or diarrhea [1][2][3][4][5].…”

Perioperative Management of Acute Appendicitis in a Patient with Glutaric Aciduria Type 1

“…These two steps are essential in treating these patients, in terms of better and many times personalized treatment that they should receive. [9][10][11][12][13] The postoperative course of these patients is almost as important as the pre-and intraoperative course. These patients should be closely monitored for postoperative complications such as hemorrhage or infections, which can again trigger a new crisis.…”

Perioperative Management of a Patient With Glutaric Aciduria

“…The estimated prevalence varies from 1 in 30,000 newborns in one Scandinavian study to 1 in 30,000 -100,000 newborns in other studies [2][3][4][5]. The prevalence may be much higher in isolated populations in the Middle East countries due to higher rates of consanguinity [6,7]. GA-1 was described first by Goodman et al in 1975 [8].…”