Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?

Abstract

Enzyme defects of the urea cycle typically present with significant hyperammonemia and its associated toxicity, in the first few months of life. However, arginase I (ARG1) deficiency, a rare autosomal recessive disorder, has classically been the exception. ARG1 deficiency usually presents later in life with spasticity, seizures, failure to thrive and developmental regression. Neonatal and early infantile presentation of ARG1 deficiency with severe hyperammonemia remains rare and only six such cases have been described. We report a severely affected infant with ARG1 deficiency who presented at 6 weeks of age with lethargy, poor feeding and severe encephalopathy caused by hyperammonemia. The clinical and biochemical features of the proband and six other previously reported cases with neonatal or infantile-onset presentation of ARG1 deficiency with hyperammonemia are reviewed. In addition, the clinical spectrum of seven previously unpublished patients with later onset ARG1 deficiency, who also experienced recurrent hyperammonemia, is presented. Several biochemical abnormalities have been postulated to play a role in the pathogenesis of the neurological changes in ARG1 deficiency including hyperargininemia, elevated guanidino compounds and elevated glutamine levels, as well as the hyperammonemia. The index case demonstrated many of these. The cases reviewed here suggest a genotype/phenotype correlation and advocate for the addition of arginine as a primary target in newborn screening programs.

Figure 1

MRI brain of index case at 24 hours post presentation. a) T2W image demonstrates diffuse abnormally increased signal intensity of the deep and central white matter. b) MRS (TE 35) demonstrates marked increase in the GLX/GLU peaks as indicated by the arrow c) DWI and d) ADC maps show extensive involvement of the deep white matter tracts and the juxtacortical white matter in the depths of the sulci. ADC confirms diffusion restriction.

Figure 2

Proband's glutamine, arginine and ammonia levels over the first 18 month of life.

Figure 3

Proband's plasma ornithine and urine orotic acid levels. X and Y axis are not to scale. Numbers in small boxes refer to level of urine orotic acid. The break in the Orotic acid line (=) implies unavailable data for urine orotic acid from 4 to 14 months of life.