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J Inherit Metab Dis. 2017 May;40(3):357-368. doi: 10.1007/s10545-017-0022-x. Epub 2017 Mar 1.

Expanding the phenotype in argininosuccinic aciduria: need for new therapies.

Author information

1
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK. julien.baruteau@gosh.nhs.uk.
2
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK. julien.baruteau@gosh.nhs.uk.
3
Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK. julien.baruteau@gosh.nhs.uk.
4
Metabolic Medicine Department, Royal Manchester Children Hospital NHS Foundation Trust, Manchester, UK.
5
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, WC1N 3JH, London, UK.
6
Metabolic Medicine Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
7
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK.
8
North East Thames Regional Genetic Services, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
9
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
10
Metabolic Medicine Department, Evelina Children's Hospital, London, UK.
11
Metabolic Medicine Department, St Thomas Hospital, London, UK.
12
Paediatric Metabolic Medicine, Royal Hospital for Sick Children, Glasgow, UK.
13
Neuroradiology Department, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
14
Neuroradiology Department, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
15
Population, Policy and Practice Programme, UCL Institute of Child Health, London, UK.
16
West Midlands Regional Genetic Laboratory, Birmingham Women's Hospital, Birmingham, UK.
17
Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
18
Genetics and Genomic Medicine Programme, Great Ormond Street Institute of Child Health, University College London, London, UK.
19
MRC Laboratory for Molecular Cell Biology, University College London, London, UK.

Abstract

OBJECTIVES:

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.

METHODS:

Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
28251416
PMCID:
PMC5393288
DOI:
10.1007/s10545-017-0022-x
[Indexed for MEDLINE]
Free PMC Article

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