Argininemia: Pathophysiology and Novel Methods for Evaluation of the Disease

Argininemia or arginase-1 deficiency constitutes a rare, genetic, metabolic disorder caused by mutations in arginase 1—the last enzyme of the urea cycle—that hydrolyses L-arginine to ornithine and urea. The disease is associated with progressive development of spasticity and other symptoms, including seizures, developmental delay, cognitive impairment, and hepatic pathology. The present review attempts to summarize the current knowledge on the pathophysiology of the disease and highlight novel methods for its evaluation. Different factors, such as the accumulation of arginine, ammonia, and guanidino compounds, act as neurotoxins and may account for the neurological sequelae observed in the disease. New markers, such as arginine/ornithine ratio along with metabolomics, machine learning algorithms, and genetic methods, can be useful in the early diagnosis of argininemia, while mobile phone apps can assist argininemic patients in adhering to the strict diet required. Neurophysiology, multi-modal imaging, and new modelling methods, such as induced pluripotent stem cells, hold promise for providing new insights into the pathophysiology of the disease. There are still many uncertainties regarding the underlying mechanisms of argininemia, but the use of novel modelling methods and new technology can lead to the decipherment of its pathophysiology, improvement of diagnostic accuracy, and better disease management.