Expanding the phenotype in argininosuccinic aciduria: need for new therapies

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.