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Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO\u2010mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration\u2010related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia\/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide <jats:sup>123<\/jats:sup>I\u2010ioflupane, in <jats:italic>Asl<\/jats:italic>\u2010deficient mice treated by <jats:italic>hASL<\/jats:italic> mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal <jats:sup>123<\/jats:sup>I\u2010ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late\u2010onset movement disorder with cell\u2010autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.<\/jats:p>","DOI":"10.1002\/jimd.12691","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T08:25:37Z","timestamp":1701678337000},"page":"1213-1227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria"],"prefix":"10.1002","volume":"47","author":[{"given":"Sonam","family":"Gurung","sequence":"first","affiliation":[{"name":"Great Ormond Street Institute of Child Health University College London  London 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