title: Expanding the phenotype in argininosuccinic aciduria: need for new therapies.
abstract: This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.
  
  
  
  Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.
  
  
  
  Fifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0-53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like 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-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.
  
  
  
  Our study further defines the natural history of argininosuccinic aciduria and genotype-phenotype 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.
authors.affiliation: Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK. julien.baruteau@gosh.nhs.uk.|Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK. julien.baruteau@gosh.nhs.uk.|Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK. julien.baruteau@gosh.nhs.uk.
authors.forename: Julien
authors.identifier: 0000-0003-0582-540X
authors.initials: J
authors.lastname: Baruteau
authors.affiliation: Metabolic Medicine Department, Royal Manchester Children Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jameson
authors.affiliation: Metabolic Medicine Department, Royal Manchester Children Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.|Metabolic Medicine Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
authors.affiliation: Metabolic Medicine Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Metabolic Medicine Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Suresh
authors.initials: S
authors.lastname: Vijay
authors.affiliation: Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK.
authors.forename: Huriye
authors.initials: H
authors.lastname: Kocadag
authors.affiliation: North East Thames Regional Genetic Services, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Beesley
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Cleary
authors.affiliation: Metabolic Medicine Department, Evelina Children's Hospital, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Mundy
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Abulhoul
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.|Metabolic Medicine Department, Royal Manchester Children Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Broomfield
authors.affiliation: Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Lachmann
authors.affiliation: Metabolic Medicine Department, St Thomas Hospital, London, UK.
authors.forename: Yusof
authors.initials: Y
authors.lastname: Rahman
authors.affiliation: Paediatric Metabolic Medicine, Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Robinson
authors.affiliation: Neuroradiology Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: MacPherson
authors.affiliation: Neuroradiology Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Foster
authors.affiliation: Neuroradiology Department, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.affiliation: Population, Policy and Practice Programme, UCL Institute of Child Health, London, UK.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ridout
authors.affiliation: West Midlands Regional Genetic Laboratory, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Kirsten McKay
authors.initials: KM
authors.lastname: Bounford
authors.affiliation: Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK.|Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.affiliation: Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.|Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK.|MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Davison
mesh_terms: D000293:Adolescent; D000328:Adult; D000641:Ammonia / Q000378:metabolism; D001125:Argininosuccinic Acid / Q000097:blood; D056807:Argininosuccinic Aciduria / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D001125:Argininosuccinic Acid; D000641:Ammonia