Relationship between elevated arginine and pathophysiology of progressive disease in arginase 1 deficiency

Arginase 1 deficiency (ARG1-D; OMIM #207800) is a rare urea cycle disorder caused by loss of arginase activity, preventing the hydrolysis of arginine to ornithine and urea. The resulting hyperargininaemia leads to accumulation of neurotoxic metabolites including guanidino compounds and nitric oxide in the central nervous system. Nervous system structures are affected, including the corticospinal tracts, cerebral and cerebellar white matter, basal ganglia, hippocampus, and corpus callosum. Clinically, patients present with developmental and neurological impairment, including growth delay, spasticity, balance and coordination challenges, seizures, and cognitive dysfunction. Without effective treatment, symptoms worsen, leading to disability, reduced quality of life, and risk of premature death.

Persistent elevation of arginine and its metabolites drives pathology. Unlike other urea cycle disorders, neurological damage in ARG1-D is largely independent of hyperammonaemia. Excess arginine increases nitric oxide production and formation of peroxynitrite, promoting oxidative stress, mitochondrial dysfunction, and reduced ATP availability. These effects impair oligodendrocyte maturation and myelination, affecting corticospinal tracts. Supraphysiologic concentrations of arginine also result in accumulation of neurotoxic metabolites including guanidino compounds which in vitro inhibit Na⁺/K⁺-ATPase activity, disrupt membrane stability, and impair inhibitory neurotransmission. The resulting hyperexcitability contributes to seizures and progressive neuromotor decline. Structural imaging demonstrates cerebral and cerebellar atrophy, white matter dysmyelination, and thinning of the corpus callosum. Electrophysiological studies show slowed neural conduction. Notably, neurological manifestations often occur despite normal ammonia concentrations, supporting hyperargininaemia and its metabolites as the primary driver of progression.

Chronic neurotoxicity from elevated arginine and its derivatives drives the progressive neurological decline in ARG1-D. Until recently, liver transplantation was the only intervention to halt progression of the disease, but it is not available to the majority of patients, is high risk, and resource intensive. In recently conducted clinical studies, enzyme therapy with pegzilarginase has demonstrated substantial reductions in arginine and its derivatives with improved clinical outcomes.