Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I

Abstract

The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I.