Is it time to start to consider treating the liver in glutaric aciduria type 1?

Glutaric aciduria type 1 (GA1) is one of the classic organic acidurias. It is caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Since its first description by Dr. Goodman almost five decades ago, tremendous progress has been made and newborn screening and treatment have improved patient outcomes. It is generally accepted that the typical acute encephalopathic crises in GA1 are caused by local cerebral generation and entrapment of toxic metabolites such as glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA). This concept was based on two key findings. Brain samples from patients with GA1 showed marked elevations of GA and 3-OH-GA,1 contrasting with the lower concentrations in plasma. A liver-specific GA1 mouse model generated through hepatocyte transplantation had elevated concentrations of GA in liver, plasma, and urine, but not in brain, which was interpreted as an indication of low permeability of the blood–brain barrier for dicarboxylic acids such as GA.2 These mice, however, had wild-type GCDH in the brain, which may have curbed the accumulation of GA and 3-OH-GA. It is thought that dietary lysine restriction and emergency intervention minimize the entry of lysine into the brain and therefore the cerebral de novo generation of toxic lysine-derived metabolites. In recently published work, Barzi et al. added a twist to our understanding of GA1 pathophysiology.3 A GA1 mouse model transplanted with wild-type hepatocytes survived exposure to a high protein diet, whereas the nontransplanted mice died as expected. A series of cleverly designed follow-up experiments all confirmed that the toxic metabolites are produced by the liver and thus are able to cross the blood–brain barrier to exert their detrimental effect. The authors also inhibited the hepatic lysine catabolism upstream of GCDH through deletion of Aass, encoding aminoadipate-semialdehyde synthase (AASS), which resulted in normalization of GA and 3-OH-GA and survival despite exposure of the GA1 mice to a high protein diet. These new data are important and suggest that liver-directed therapeutic approaches may be useful in GA1. These include gene therapy, but also substrate reduction through RNAi-mediated or pharmacological inhibition of AASS. This new study does not offer an explanation for the remarkably high concentration of GA and 3-OH-GA in the brain of patients nor does it explain the remarkable specific toxicity in the striatum. Although these results are compelling, this study was done in mice, and confirmation in other model systems is still needed before concluding that these treatments will likely translate to patients. Recent progress in the study of disorders of lysine metabolism is paving the way for the development of new treatment options for patients with GA1 as well as other lysine metabolism disorders such as pyridoxine-dependent epilepsy caused by pathogenic variants in ALDH7A1. To facilitate the development of these therapies, clinical studies addressing long-term complications and outcome in patients are needed.