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Arginase 1 Deficiency (ARG1-D) is a rare inborn error of metabolism and distinct urea cycle disorder (UCD) that results in persistent hyperargininemia. Unlike the typical presentation of UCDs, individuals with ARG1-D appear healthy at birth, symptomatic hyperammonemia is less common, and onset of clinical manifestations occurs during the first years rather than days of life, suggesting a distinct mechanism of disease.

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Mouse models of ARG1-D demonstrate high plasma arginine (pArg), neurologic abnormalities, and gait abnormalities, providing empirical evidence for arginine as the driver of disease manifestations. Due to the rarity of ARG1-D, clinical evidence is largely anecdotal and based on individual cases or sibling series. Nonetheless, a clear pathophysiological profile has emerged: high pArg is associated with progressive spasticity, intellectual disability, global developmental delay, and seizures. Severe dietary protein restriction to minimize exogenous arginine is the mainstay of care and, although few patients achieve goal levels and all patients deteriorate over time, lowering arginine improves outcomes. Treatment from birth lessens or delays progression, and treatment lapses in older patients with established disease result in worsening of intellectual and mobility impairments that subsequently improve upon reinstatement of therapy. These observations are supported by the first clinical trials of a human enzyme therapy for ARG1-D, which demonstrated significant reduction in pArg accompanied by clinically meaningful improvement in mobility.

Taken together, available evidence implicates high arginine as the primary driver of pathology in this progressive and debilitating disorder and emphasizes the need for sustained reduction of arginine levels in patients with ARG1-D.