Hyperargininemia: A Family with a Novel Mutation in an Unexpected Site
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.
KeywordsCerebral Palsy International Normalize Ratio Urea Cycle Arginase1 Activity Spastic Paraparesis
- Brusilow SW, Horwich AL (2001) Urea cycle enzymes. In: Sriver CR, Baudet AL, Sly WS, Valle D (eds) The metabolic bases of inherited diseases, 8th edn. McGraw-Hill, New York, pp 1909–1963Google Scholar
- De Deyn PP, Marescau B, Qureshi IA (1997) Hyperargininemia: A treatable inborn error of metabolism? In: De Deyn PP, Marescau B, Qureshi IA et al (eds) Guanidino compounds in biology and medicine, vol 2. John Libbey & Company Ltd, London, pp 53–69Google Scholar
- Gomes Martins E, Santos Silva E, Vilarinho S, Saudubray JM, Vilarinho L (2011) Neonatal cholestasis: an uncommon presentation of hyperargininemia. J Inhert Metab Dis. [Epub ahead of print] doi: 10.1007/s10545-10-9263-7, Jan 13 OnlineGoogle Scholar