# Clinical Characteristics of Arginase 1 Deficiency: Natural History Insights From International Clinical Trials

## TL;DR

This study provides insights into the clinical features and progression of Arginase 1 deficiency, a rare metabolic disorder, based on data from the largest cohort studied to date.

## Contribution

The study presents the largest and most comprehensive analysis of clinical characteristics in Arginase 1 deficiency patients.

## Key findings

- Symptoms typically begin at age 2.2 years, with diagnosis occurring at 3.7 years on average.
- Patients show a range of neurological impairments, including motor issues, cognitive deficits, and speech problems.
- Quality of life scores were significantly lower compared to typically developing peers.

## Abstract

Arginase 1 deficiency (ARG1‐D) is an ultra‐rare inherited metabolic disorder of the urea cycle, caused by partial or complete loss of arginase 1 function, characterised by hyperargininaemia and a distinct, progressive neurological phenotype. The clinical development programme of pegzilarginase, a recombinant human ARG1 enzyme therapy, provides an opportunity to study the largest ARG1‐D cohort to date. The analysis included 48 paediatric and adult subjects (≥ 2 years) enrolled in the pegzilarginase trials. Baseline data collected before treatment included demographics, genotypes, red blood cell arginase activity, biochemical measures, age of symptom onset, neuromotor and neurological characteristics, growth indicators, quality of life, and use of treatments and assistive devices. The mean (SD) age of onset was 2.2 (3.6) years, which preceded diagnosis at 3.7 (5.0) years. Clinical features included motor impairment (48/48, 100%), spasticity (33/48, 69%), cognitive deficits (31/48, 65%), intellectual disability (23/36, 64%), speech and language deficits (26/48, 54%), and seizures (18/48, 38%), with symptom‐onset data consistent with a progressive phenotype. Median GMFCS Level II indicated moderate mobility limitation; two‐thirds scored < 69 on FSIQ, and mean PedsQL total proxy scores were around 20% lower than typically developing peers. All subjects followed a protein‐restricted diet, and 90% used ammonia scavengers. ARG1‐D presents with a heterogeneous array of progressive and debilitating neurologic symptoms. These findings reflect the progressive impact of the disease and offer insights into its burden and natural history based on a large cohort, assessed using standardised neuromotor, cognitive, and quality‐of‐life instruments across international sites.