Abstract

Arginase 1 deficiency (ARG1-D) is a rare urea cycle disorder primarily affecting the central nervous system with progressive spasticity, cognitive decline, and variable seizures, despite often mild hyperammonemia. Conventional treatment fails to maintain optimal metabolic control, leading to irreversible functional impairment. Pegzilarginase, a pegylated recombinant human ARG1 enzyme, has recently emerged as a causal therapy capable of reducing plasma arginine and improving motor outcomes, marking a new era in disease-modifying interventions.
This expert opinion paper, authored by an Italian multidisciplinary panel – including clinicians with real-world and trial-based experience – aims to harmonize diagnostic and follow-up strategies in ARG1-D. Based on literature review, clinical experience, and evidence from the PEACE trial, the panel proposes a multidomain clinical framework integrating core, advanced, and exploratory assessments across biochemical, neuromotor, imaging, hepatic, musculoskeletal, and quality-of-life domains.
The proposed model includes essential tools such as plasma arginine and guanidino compounds monitoring, standardized motor function scales (GMFM, GMFCS), MRI, and cognitive assessments. Optional investigations like cerebrospinal fluid (CSF) arginine, proton magnetic resonance spectroscopy (¹H-MRS), and motor evoked potentials offer mechanistic insights, while exploratory biomarkers [e.g., growth differentiation factor 15 (GDF15), neurofilament light chain] may refine understanding of redox-autophagic mechanisms and functional recovery. The paper highlights unmet needs, including muscle fibrosis and autophagy modulation by arginine, with implications for both pathogenesis and treatment response.
This framework serves as a foundation for future national guidelines and research. By fostering standardized, evidence-based care and embedding advanced tools in routine practice, it aims to improve outcomes for current and future patients with ARG1-D, transforming the natural history of this previously relentless disorder through expert collaboration and innovation.