CO1 The Natural History, Clinical Outcomes and Unmet Needs of Patients with Arginase 1 Deficiency (ARG1-D): A Systematic Review of Case Reports

Abstract

ARG1-D is a debilitating, progressive, inherited, metabolic disease characterized by hyperargininemia leading to significant morbidity and early mortality. The objective of this study was to systematically review the literature to assess the natural history, clinical outcomes, and unmet needs of patients with ARG1-D. We searched MEDLINE, EMBASE, and other databases for case reports describing patients with ARG1-D. Eligible studies reported natural history (patient demographics, diagnosis methods, clinical manifestations), treatments, and/or clinical outcomes (cognitive, motor, growth, death). Two individuals independently screened records, extracted data, and assessed study quality using the Joanna Briggs Institute Critical Appraisal Tool. We included 90 studies that described 157 unique patients with ARG1-D. The most frequently reported and observed clinical manifestations were motor deficits (126/133; 95%), including lower limb spasticity (102/114; 89%); intellectual disability or cognitive impairment (87/112; 78%); and seizures (78/101; 77%). Most clinical manifestations were documented by 3 years of age; mean age of diagnosis was 6.4 years (median 5; range 0-27). Physician-prescribed dietary restriction was the most commonly reported intervention (62%), followed by use of nitrogen scavengers (45%), essential amino acids (21%), dialysis (5%), and liver transplantation (3%). Few studies reported clinical outcomes: 23 reported motor function (11 patients improved, 12 did not), 19 reported cognitive function (15 patients improved, 4 did not), and 10 reported growth (6 patients improved, 4 did not). Sixteen patients died, all but one before 25 years and six before age 2. This review describes the natural history of ARG1-D in terms of clinical presentation and diagnosis. It illustrates that the current standard of care is ineffective at managing the disease and does not improve clinical outcomes. The large sample of included cases highlights a significant disease burden, risk of mortality, and a clear unmet need for clinically effective treatment options for patients with ARG1-D.