The role and control of arginine levels in arginase 1 deficiency

Abstract

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.

Keywords: arginase deficiency; guanidino compounds; hyperargininemia; inborn error of metabolism; urea cycle disorder.

FIGURE 1

Urea Cycle Dysfunction in Arginase 1 Deficiency. Loss of arginase 1 enzymatic activity results in pathologic accumulation of arginine, decreased levels of its urea cycle products (ornithine and urea), and increased levels of guanidino compounds. ARG1, arginase 1; ASL1, argininosuccinate lyase; ASS1, argininosuccinate synthetase 1; ORNT1, ornithine transporter 1. Adapted with permission from Blair NF, Cremer PD, and Tchan MC. Pract Neurol. 2015;15:45–48. doi:10.1136/practneurol‐2014‐000916

FIGURE 2

Plasma Arginine Levels With Current Standard of Care. Analysis of data from patients (n = 22) with Arginase 1 Deficiency in the Urea Cycle Disorder Consortium database. Dashed line indicates upper limit of normal applied to the study's laboratory assessments; current guidelines recommend maintaining plasma arginine <200 μmol/L. Blue dots represent arginine levels below the applied upper limit of normal of 150 μmol/L. Adapted with permission from Burrage LC, Sun Q, Elsea SH, et al. Hum Mol Genet. 2015;24 (22):6417–6427. doi:10.1093/hmg/ddv352