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Review
. 2025 Sep;46(9):4219-4228.
doi: 10.1007/s10072-025-08153-3. Epub 2025 Apr 16.

Arginase 1 deficiency: a treatable form of spastic paraplegia

Alessandro Burlina  1 , Anna Ardissone  2 , Roberta Battini  3   4 , Alberto Burlina  5 , Serena Gasperini  6 , Andrea Pession  7 , Francesco Porta  8 , Carlo Dionisi Vici  9
Affiliations
Review

Arginase 1 deficiency: a treatable form of spastic paraplegia

Alessandro Burlina et al. Neurol Sci. 2025 Sep.

Abstract

Background: Arginase 1 deficiency (ARG1-D) is a rare hereditary urea cycle disorder characterized by elevated arginine levels, resulting in progressive neurological impairment and severe physical and cognitive disability. Due to its low prevalence, overlapping symptoms with other neurological disorders, and current limitations in newborn screening tools, ARG1-D is often misdiagnosed or diagnosed late, limiting access to early interventions.

Aim: This review and expert opinion aim to provide an overview of the clinical manifestations, diagnostic challenges, and treatment options for ARG1-D, offering a practical resource for specialists to recognize this rare, progressive, yet treatable disease.

Results: ARG1-D typically presents with progressive spastic paraplegia, developmental delays, cognitive impairment, and seizures, with symptom onset and severity varying by age. Differential diagnoses mainly include hereditary spastic paraplegia, cerebral palsy, and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, each with distinct clinical features and biochemical markers. Potential red flags for ARG1-D include elevated plasma arginine levels, spasticity, seizures, and cognitive impairment. These should prompt further examinations to confirm the diagnosis, which is based on biochemical assays for hyperargininemia and on genetic testing. Once confirmed, early treatment is advised, including dietary protein restriction, ammonia scavengers, antiepileptic drugs, and novel therapies, such as pegzilarginase, which targets the disease's metabolic root.

Conclusion: Experts stress the importance of increased awareness of ARG1-D characteristics, noting that early recognition and treatment are crucial to patient outcomes. Greater recognition of ARG1-D's distinctive features, differential diagnosis, and diagnostic tools, even among non-specialist clinicians, could help prevent misdiagnoses and facilitate the identification of this rare yet treatable condition.

Keywords: Arginase 1 deficiency; Differential diagnosis; Neurological impairment; Spastic paraplegia; Urea cycle disorder.

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Conflict of interest statement

Declarations. Ethical approval: Not applicable. Conflicts of interest: None.

Figures

Fig. 1
Fig. 1
Age of onset of clinical manifestations and diagnosis. Adapted from Bin Sawad 2022 [7]; published open access under the terms of the Creative Commons Attribution License
See this image and copyright information in PMC

References

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