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Blinded review of brain MRIs. <jats:italic>ASL<\/jats:italic> genotyping.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifty\u2010six patients were defined as early\u2010onset (<jats:italic>n<\/jats:italic>\u2009=\u200923) if symptomatic\u2009&lt;\u200928 days of age, late\u2010onset (<jats:italic>n<\/jats:italic>\u2009=\u200923) if symptomatic later, or selectively screened perinatally due to a familial proband (<jats:italic>n<\/jats:italic>\u2009=\u200910). The median follow\u2010up was 12.4 years (range 0\u201353). Long\u2010term outcomes in all groups showed a similar neurological phenotype including developmental delay (48\/52), epilepsy (24\/52), ataxia (9\/52), myopathy\u2010like symptoms (6\/52) and abnormal neuroimaging (12\/21). Neuroimaging findings included parenchymal infarcts (4\/21), focal white matter hyperintensity (4\/21), cortical or cerebral atrophy (4\/21), nodular heterotopia (2\/21) and reduced creatine levels in white matter (4\/4). 4\/21 adult patients went to mainstream school without the need of additional educational support and 1\/21 lives independently. Early\u2010onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early\u2010onset and half of late\u2010onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. <jats:italic>ASL<\/jats:italic> was sequenced (<jats:italic>n<\/jats:italic>\u2009=\u200919) and 20 mutations were found. Plasma argininosuccinate was higher in early\u2010onset compared to late\u2010onset patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study further defines the natural history of argininosuccinic aciduria and genotype\u2013phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-017-0022-x","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T13:38:44Z","timestamp":1488375524000},"page":"357-368","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Expanding the phenotype in argininosuccinic aciduria: need for new therapies"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-540X","authenticated-orcid":false,"given":"Julien","family":"Baruteau","sequence":"first","affiliation":[{"name":"Gene Transfer Technology Group, Institute for Women's Health University College London London UK"},{"name":"Metabolic Medicine Department Great Ormond Street Hospital for Children NHS Foundation Trust Great Ormond Street London WC1N 3JH UK"},{"name":"Genetics and Genomic Medicine Programme, Great Ormond Street 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