Expanding the phenotype in argininosuccinic aciduria: need for new therapies

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.

Fig. 1

Neuroimaging. A: Morphological brain MRI features. A, B: T2-weighted axial images showing brain matter volume loss and mild ex vacuo dilatation of ventricles (A) and high signal in bilateral caudate heads and posterior putamina (arrows). C: T2-weighted axial images with severe diffuse cerebral atrophy and ventricular dilatation. D, H: T1-weighted coronal image with right periventricular heterotopia (arrowheads). E, F: T2-weighted axial (E) and coronal (F) images with evidence of right inferior frontal lobe infarct (arrow). G: T2-weighted axial image with bilateral high signal of the peritrigonal white matter (arrow). B ¹ H MR spectroscopy features in basal ganglia. Assessment in early-onset (n = 5), late-onset (n = 3) and control (n = 63) patients analysed using a paired t test. c ¹ H MR spectroscopy features in white matter. Patients affected by argininosuccinic aciduria (n = 4) and controls (n = 53) analysed with one way ANOVA. Graphs represent mean ± 95% confidence interval. * p < 0.05; ** p < 0.01

Fig. 2

Natural history of argininosuccinic aciduria. A Kaplan-Meier survival curves for all (solid line), early-onset (dashed line), late-onset (dashed dotted line) and screened (dotted line) patients. B Natural history of the systemic phenotype of argininosuccinic aciduria. Mean ± standard error of age of onset of each symptom from data of the whole cohort when information available: developmental delay (n = 7), abnormal LFTs (n = 8), hepatomegaly (n = 18), epilepsy (n = 15), brittle hair (n = 4), ataxia (n = 6), hypokalaemia (n = 2), high blood pressure (n = 1). Symptom frequency in the total population of patients studied is presented in brackets. ALT: plasma alanine aminotransferase activity. It was assumed that patients had normal blood pressure if hypertension was not specifically mentioned in medical records