Clinical status, biochemical profile and management of a single cohort of patients with arginase deficiency

Abstract

Arginase deficiency is a rare autosomal recessive urea cycle disorder (UCD) caused by mutations in the ARG1 gene encoding arginase that catalyses the hydrolysis of arginine to ornithine and urea. Patients have hyperargininaemia and progressive neurological impairment but generally suffer fewer metabolic decompensations compared to other UCDs. The objective is to describe the clinical features, biochemical profile, neuroradiological findings and experience of managing children with arginase deficiency. Twenty-year retrospective review of patient medical records at a single metabolic centre was performed. Six patients from three unrelated families were identified. Mean age at first symptom was 3.3 (1.5-9.0) years, while mean age at diagnosis was 8.8 (0.16-15.92) years. Four patients developed spastic diplegia and two of six with spastic quadriplegia with classical features including hyperreflexia, clonus and toe walking. This resulted in gait abnormalities that have been monitored using the GAITRite system and required Achilles tendon release in five children. Generalised tonic-clonic seizures and/or absences were present in three of six children and were controlled with anticonvulsants. All patients had moderate learning difficulties. Neuroimaging showed cerebral/cerebellar atrophy in four patients and basal ganglia abnormalities in two. Arginine levels were universally elevated throughout follow-up despite protein restriction, essential amino acid supplementation and ammonia scavengers, and neurological outcome was generally poor. Two patients died following severe metabolic decompensation in adolescence. Children with arginase deficiency continue to present a management challenge of what appears to be an inexorable course of neurocognitive impairment. Further insight into disease mechanisms may provide insight into novel treatment strategies.

Keywords: arginase deficiency; hyperammonaemia; metabolic decompensation; trial end points; urea cycle disorder.

FIGURE 1

Biochemical data for the six patients. Arginine and ammonia levels (umol/L) followed up over time (age/years). For Patients 2.1 and 2.2, there are no data points between the ages of 7–12 years and 2–7 years, respectively, as they have been lost to follow‐up. In all patients, arginine levels were above the target of 200umol/L virtually throughout follow‐up. Arginine and ammonia levels were both seen to increase steeply from baseline during metabolic decompensations. B, Regular sodium benzoate commenced; P regular sodium phenylbutyrate commenced; * metabolic decompensation

FIGURE 2

Gait velocity (A,B), cadence (C,D), base of support (E,F) and step length (G,H) measured using GAITRite system plotted on paediatric centiles. Patients 1.1, 1.2, 2.1 and 2.2 plotted on female centile curves and Patient 1.3 on male centile curves. Centile extremes correspond to the 0.5th and 99.5th centiles. Footstep analysis for Patient 1.1 before (I) and after (J) Achilles tendon release surgery demonstrating significant improvement of gait symmetry and contact surface area