Arginase Deficiency

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Arginase deficiency (AD) is inherited as an autosomal recessive disorder resulting from mutations in the arginase gene. Humans express two distinct arginase genes identified as ARG1 and ARG2 that encode the arginase type I and type II enzymes, respectively. The ARG1 gene encoded protein is the cytoplasmic liver enzyme contributing 98% of the urea cycle arginase activity in that organ. ARG2 encodes a mitochondrial arginase found predominately in the kidneys. The ARG1 gene is located on chromosome 6q23 and is composed of 8 exons that generate two alternatively spliced mRNAs. One of these mRNAs encodes a protein of 330 amino acids (isoform 1) and this protein is often referred to as the erythroid variant. The other ARG1-derived mRNA encodes a protein of 322 amino acids. The functional arginase enzyme exists as a homotrimer. Mutations in ARG1 give rise to hyperargininemia also known as arginase deficiency (AD). Mutations in ARG1 gene are rare and the frequency of AD is approximately 1 per 363,000 live births. The ARG2 gene is located on chromsome 14q24.1 and is composed of 8 exons that encode a protein of 354 amino acids. Although the precise function of the ARG2 encoded enzyme (arginase type II) remains unclear it is thought to play a role in nitric oxide (NO) and polyamine metabolism.

The major symptoms of AD are all progressive and include psychomotor retardation, spastic tetraplegia where the lower limbs are more affected than the upper, hyperactivity, growth failure and seizures. Because arginase catalyzes the last reaction of the urea cycle, hyperammonemia is not as severe as in other neonatal UCDs (3-4 times normal as opposed to 6 times normal in say OTCD). The most prominent laboratory findings in AD are mild hyperammonemia, hyperargininemia, hyperaminoaciduria (arginine, lysine, ornithine and cystine) and orotic aciduria.

AD patients are treated in much the same ways as for other neonatal UCDs in that protein intake must me highly regulated and the hyperammonemia must be controlled. Hemodialysis is the only effective means to rapidly lower serum ammonia levels in these patients. Acute episodes of hyperammonemia can be treated with intravenous administration of Ammunol® and with oral Buphenyl® for chronic adjunctive therapy of hyperammonemia.












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Last modified: May 22, 2015