Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site

Abstract

Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from other urea cycle defects by a progressive paraparesis of the lower limbs (spasticity and contractures) with hyperreflexia, neurodevelopmental delay and regression in early childhood. Growth is affected as well. Hyperammonemia is episodic, if present at all. The disease is caused by mutations in the ARG1 gene; there are approximately 20 different known ARG1 mutations with considerable genetic heterogeneity. We describe two Arab siblings with a late diagnosis of hyperargininemia and present the genetic findings in their family. As ARG1 sequencing was unrevealing despite suggestive clinical and laboratory findings, molecular cDNA analysis was performed. The ARG1 expression pattern identified a 125-bp out-of-frame insertion between exons 3 and 4, leading to the addition of 41 amino acids and a premature termination codon TGA at the sixth codon downstream. The insertion originated at intron 3 and was attributable to a novel c.305 + 1323 t > c intronic base change that enabled an enhancement phenomenon. This is the first reported exon-splicing-enhancer mutation in patients with hyperargininemia. The clinical course and genetic findings emphasize the possibility that hyperargininemia causes neurological deterioration in children and the importance of analyzing the expression pattern of the candidate gene when sequencing at the DNA level is unrevealing.

Competing interests: None declared.

Appendices

Take Home Message

A late diagnosis of hyperargininemia should be considered in pediatric patients with neurodevelopmental delay and regression in early childhood.

When cDNA sequencing is unrevealing, the expression pattern of the candidate gene should be analyzed for identification of potential novel mutations.

Details of Contributors

• 1. Dr. Haimi-Cohen collected and analyzed the clinical data, described the patients, and drafted and edited the manuscript.

• 2. Mrs. Bargal conducted and interpreted the molecular analysis and described the genetic findings in the manuscript.

• 3. Dr. Zeigler supervised the molecular analysis investigation and contributed significantly in interpreting the data and revising the manuscript.

• 4. Dr. Eidlitz-Markus helped in the collection and analysis of the clinical data and made a great contribution to the writing of the manuscript.

• 5. Mrs. Zuri contributed to all stages of the molecular analysis and the interpretation of its results and assisted in revising the manuscript.

• 6. Dr. Zeharia initiated the study. He contributed substantially to coordination of the clinical and molecular data of the study, to its design, and to the revision of the manuscript.

Guarantor of Study

Yishai Haimi-Cohen

Patient Consent

Not applicable

Competing Interests

None of the authors has a conflict of interest.

Funding

No funding was received for this study.