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At a glance

Urea cycle disorder that leads to hyperammonemia and neurologic symptoms, which are less severe than in other forms of urea cycle abnormalities.

Synonyms

Arginase Deficiency; Hyperargininemia; ARG1-Deficiency.

Incidence

Estimated in the range of 1:350,000-2,000,000 live births. A higher incidence has been reported from certain parts in Japan and Quebec (Canada). No sexual predilection.

Genetic inheritance

Autosomal recessive. Numerous mutations have been mapped to chromosome 6q23.

Pathophysiology

The hepatic urea cycle is the main pathway for the metabolism and elimination of proteins and amino acids. The urea cycle consists of six sequential enzymatic steps with the goal to convert nitrogen derived from proteins and amino acids to urea. The first three enzymatic steps (N-acetyl glutamate synthase, carbamoyl phosphate synthase, and ornithine transcarbamylase) take place in the mitochondrion and lead to the formation of citrulline, which then leaves the mitochondrion for the cytoplasm to eventually get converted to urea (with argininosuccinate synthase, argininosuccinate lyase, and arginase 1, ARG1). ARG1 is the last enzyme in this circle where on the one hand the hydrolytic cleavage of the guanidine group from arginine allows for the formation of urea and on the other hand for the conversion of arginine to ornithine, which then reenters the mitochondrion, where it can get converted back to citrulline again. There are two isoenzymes of arginase, ARG1 (found in the liver, erythrocytes, and salivary glands), and arginase 2 (ARG2) (located in the kidneys) originating from separate gene loci, called ARG1 (located on chromosome 6q23) and ARG2 (on chromosome 14q24.1). The ARG1 isoenzyme is responsible for 98% of the arginase activity in the liver and its lack results in argininemia. ARG2 is inducible, and its activity can increase up to 40-fold in patients with Argininemia. ARG2 metabolizes hepatic arginine into urea and ornithine. While the urea is excreted, the newly synthesized ornithine returns to the liver and is incorporated into the urea cycle. Hyperammonemia in arginase deficiency can potentially be severe and fatal, but is most often mild to moderate because ARG2 is inducible and thus able to compensate to some extent for the absent ARG1 function.

Diagnosis

Based on the clinical findings of delayed development, protein intolerance, spasticity, and/or a positive family history. However, these symptoms are rather unspecific and the clinical diagnosis may be difficult and missed for a significant period of time. Yet, early detection is crucial as this allows for proper diet (ie, restricted dietary protein intake with supplementation of essential amino acids and calories from carbohydrates and fat in order to reduce catabolism) and pharmacological treatment (use of oral nitrogen-scavenging drugs, see below) and thus prevention of symptoms. Good compliance with the dietary restrictions alone can improve arginine levels to almost normal in plasma (ie, 40-120 μmol/L) and cerebrospinal fluid (CSF) ...

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