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Management of Citrullinemia Type 1 due to a Kinetic Variant in Argininosuccinate Synthetase with Oral L-Aspartate

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by a deficiency in argininosuccinate synthetase (ASS1), which catalyzes the biosynthesis of argininosuccinate from citrulline and aspartate. Routine daily management typically consists of protein restriction, nitrogen scavengers, and arginine supplementation. In this case, we report management of an ASS1 kinetic variant c.352G>A p.Ala118Thr, which is found in the substrate binding site. In vitro, this variant is reported to have approximately 50% decreased enzyme activity and decreased affinity for both citrulline and aspartate. However, with high L-aspartate supplementation, enzyme activity is rescued to 99% of wild-type. 

Case Presentation
8 year-old female initially detected on newborn screen with elevated citrulline 720 umol/L.

Diagnostic Workup
Plasma amino acids showed citrulline 1700 umol/L, glutamine 1066 umol/L, and arginine 24 umol/L. Molecular testing showed compound heterozygous pathogenic variants ASS1 c.352G>A p.Ala118Thr and c.1168G>A p.Gly390Arg.

Treatment and Management
From biochemical diagnosis at 5 days old, she was managed sufficiently with a vegetarian diet and arginine, and without daily nitrogen scavengers. Her glutamine remained within normal limits with no hyperammonemic crises. At 4 years old, she began to show some aggressive behaviors in preschool, but her glutamine remained stable. Her parents expressed concern that her behaviors were caused by elevated citrulline. While there is limited evidence of this pathophysiology, given her mild presentation and the possibility that supplemental arginine could be an additional source of elevated citrulline, she was trialed off arginine and continued on vegetarian diet, which resulted in stable citrulline and glutamine, normal arginine, and age-appropriate behaviors from 4-6 years old. However, from 6-8yo, with no significant increase in her dietary protein, her glutamine began to uptrend to levels close to her initial diagnosis. She has developed no new behavior changes or metabolic crises related to increased glutamine. However, in discussion with her parents about the risks and benefits of starting an oral nitrogen scavenger vs. a trial of oral aspartate given the in vitro understanding of the p.Ala118Thr variant, she has begun a trial of oral aspartate.

Outcome and Follow-Up
Our patient has shown good tolerance of an initial low dose of L-aspartate 2g twice a day. Initial data shows downtrending glutamine level, suggesting the hypothesized response of aspartate supplementation increasing ASS1 enzymatic activity. Plasma amino acids are being monitored periodically as aspartate is being titrated as tolerated.

Discussion
With a common ASS1 pathogenic variant that eliminates enzyme activity and a kinetic variant with reduced activity, our 8 year-old patient managed with protein controlled diet and supplemental arginine in early childhood has exhibited a relatively mild phenotype with typical development and no hyperammonemic crises. However, she continues to have elevated glutamine and remains at risk for hyperammonemic crisis. To expand the options for the management of her urea cycle disorder beyond oral nitrogen scavengers and to maintain treatment sustainability, supplemental aspartate was initiated and is anticipated to improve the function of the kinetic variant and subsequently lower her glutamine.

Conclusion
Pathogenic variants in ASS1 causing citrullinemia type 1 due to decreased substrate affinity for aspartate have the potential to be managed by supplemental L-aspartate. Further study is needed in the safety and efficacy of this management approach in this subset of ASS1 variants.

Agenda

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