# Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease
## 3 Pathophysiology
### Mechanisms of the Disease  
In contrast to other UCDs, the precise pathophysiology underlying ARG1-D remains unclear with only a few things being known as to how the signs and symptoms detected in affected individuals arise. The disease is characterized by the build-up of arginine within liver cells, which is then released into plasma and accumulates in other organs. Elevated arginine levels are known to be neurotoxic [24; 41]. Arginine is a common substrate for arginase and nitric oxide synthase (NOS), thus arginase activity limits the available substrate for NO production. In arginase deficiency, excess L-arginine may trigger oxidative stress, resulting in excessive nitric oxide production. Oxidative stress in turn can reduce the activity of Na\({}^{+}\)/K\({}^{+}\)-ATPase, which is of pivotal importance for neural excitability [46]. Especially, in arginemia endothelial cells overproduce NO contributing in excessive vasodilation and enthothelium-related abnormalities, since NO plays a significant role in neurotransmission, vascular function and immune regulation [39; 47]. Concerning ammonia, it is evident that when accumulated contributes to neurological pathology by causing cerebral edema, and consequently brain damage, which mainly affects the parietal, occipital, and frontal lobes [10]. However, there is consensus on the  
Figure 1: Overview of the urea cycle, L-arginine metabolism, and associated reactions. (NAGS: N-acetylglutamate synthase, CPS1: carbamoyl phosphate synthetase 1, OTC: ornithine transcarbamylase, ORNT1: ornithine transporter 1, OAT: ornithine aminotransferase, ASS: arginininosuccinate synthase, ASL: arginininosuccinate lyase, NOS: nitric oxide synthase, AGAT: arginine:glycine amidotransferase). fact that ammonia accumulation is not the only one to be blamed for the neurological disorders observed in arginine patients, due to episodes of hyperammonemia occurring infrequently in ARG1-D [23]. Guanidino compounds, including polyamines, nitrous oxide, and agmatine, are increased in both plasma and CSF/brain tissues of patients with argininemia [48; 49]. These compounds, such as guanidinoacetic acid (GAA), \(\beta\)-guanidinopropionic acid (\(\beta\)-GPA), and \(\gamma\)-guanidinobutyric acid (\(\gamma\)-GBA), are produced through a transamidination reaction catalyzed by arginine:glycine amidotransferase (AGAT) or other types of reactions (e.g., acetylation, transamination, hydrogenation) [50]. Alongside ammonia, guanidino compounds, acting as neurotoxins, potentially contribute to the development of the neurological sequelae (e.g., spasticity, intellectual disability) observed in hyperarginineinemic patients [50; 51]. Moreover, guanidino compounds exhibit epileptogenic properties, which could be attributed to inhibition of glycine, GABA, acetylcholinesteraseerase, and butyrylcholinesterase in central nervous system, decrease in synaptosomal membrane fluidity in cerebral cortex, and reduction in the Na\({}^{+}\)/K\({}^{+}\)-ATPase activity, which causes excitotoxicity [52; 53; 54; 55]. Additionally, as observed in uremia, some guanidino compounds block transketolase activity, which may elicit demyelination and subsequently upper motor neuron signs [56]. Lastly, guanidino compounds (N-acetylarginine, arginine acid, homoarginine) along with arginine induce oxidative stress and interfere with the activity of enzymes (catalase, superoxide dismutase, glutathione peroxidase) that normally protect the brain against free radicals' damage [57]. The decrease in ornithine may impair the enzymatic activity of OTC, leading to the accumulation of aortic acid. Excess carbamoyll phosphate is then utilized in the pyrimidine synthetic pathway [58]. In addition, the reduction in mitochondrial ornithine levels may account for the oligodendrocyte degeneration, dysmyelination, and corticospinal tract immaturity found in patients with ARG1-D [59]. Various mechanisms have been proposed to explain weight differences between hyperarginine and healthy individuals.