Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Abstract

ObjectivesThis 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.MethodsRetrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.ResultsFifty-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-017-0022-x) contains supplementary material, which is available to authorized users.

Impact of Diagnosis and Therapy on Cognitive Function in Urea Cycle Disorders

“…The observed discrepancy highlights the need for a careful reevaluation of variables that are commonly used to describe disease severity and to predict survival and neurocognitive outcome. 33,34 In the future, a better understanding of genotype-phenotype correlations for ASS1-D, ASL-D, and ARG1-D will be required to provide more insight into phenotypic variability of these putatively neurodegenerative diseases. 30 Individuals suffering from ASL-D often develop impaired motor and cognitive functions and progressive hepatic disease despite metabolic control.…”

Liver neoplasms in methylmalonic aciduria: An emerging complication

“…Cases 1 to 3 showed evidence of cirrhosis/fibrosis, as previously reported in MMA and might per se increase the risk of developing liver neoplasms. Cirrhosis is a recognized complication in other inborn errors of metabolisms, such as Wilson disease, tyrosinemia type I, argininosuccinic aciduria or glycogen storage disorders; the latter three diseases identified with significant risk of developing hepatocellular carcinoma …”

Argininosuccinic aciduria fosters neuronal nitrosative stress reversed byAslgene transfer

“…Compared to other urea cycle defects, ASA patients present with an unusually high rate of neurological and systemic complications 17 contrasting with a lower rate of hyperammonaemic episodes. Various pathophysiological mechanisms have been hypothesised to account for this paradox, including impaired NO metabolism 18 . A hypomorphic Asl Neo/Neo mouse model shows impairment of both urea and citrulline-NO cycles and reproduces the clinical phenotype with impaired growth, multi-organ disease, hyperammonaemia and early death 15 .…”

“…A hypomorphic Asl Neo/Neo mouse model shows impairment of both urea and citrulline-NO cycles and reproduces the clinical phenotype with impaired growth, multi-organ disease, hyperammonaemia and early death 15 . Common biomarkers of ASA include increased ammonaemia, citrullinaemia, plasma argininosuccinic acid, orotic aciduria and reduced argininaemia 18 .…”