Arginase 1 Deficiency in Patients Initially Diagnosed with Hereditary Spastic Paraplegia

BACKGROUND: Arginase 1 Deficiency (ARG1‐D) is a rare autosomal recessive urea cycle disorder (UCD) characterized by pathologic elevation of plasma arginine and debilitating manifestations. Based on clinical commonalities and low disease awareness, ARG1‐D can be diagnosed as hereditary spastic paraplegia (HSP), leading to treatment delays. CASES: A Hispanic woman with unremarkable medical history experienced progressive lower‐limb spasticity in her 20s and received a diagnosis of HSP. She developed significant gait abnormalities and is unable to walk without assistance. More recently, two Hispanic brothers with childhood‐onset manifestations including lower‐limb spasticity, developmental delays, and seizures presented with suspected HSP. All three patients were ultimately diagnosed with ARG1‐D based on plasma arginine several‐fold above normal levels and loss‐of‐function ARG1 variants. Disease progression occurred before ARG1‐D was correctly diagnosed. LITERATURE REVIEW: Retrospective analyses demonstrate that diagnostic delays in ARG1‐D are common and can be lengthy. Because of clinical similarities between ARG1‐D and HSP, such as insidious onset and progressive spasticity, accurate diagnosis of ARG1‐D is challenging. Timely ARG1‐D diagnosis is critical because this UCD is a treatable genetic cause of progressive lower‐limb spasticity. CONCLUSIONS: Arginase 1 Deficiency should be considered in HSP differential diagnosis until biochemically/genetically excluded, and should be routinely included in HSP gene panels.