MinireviewHyperargininemia due to liver arginase deficiency
Introduction
The urea cycle is a series of six reactions that have been recruited to rid the body of waste nitrogen (Fig. 1). Arginase is the sixth and final enzyme of this cycle and the most recently evolved; the others having been present for arginine biosynthesis in lower organisms [1]. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. The first three enzymes, N-acetyl-glutamate synthase (NAGS), carbamoyl phosphate synthase I (CPSI), and ornithine transcarbamylase (OTC) function inside of the mitochondria whereas the latter three, argininosuccinic acid synthase, argininosuccinic acid lyase, and arginase, act in the cytosol [1]. At least two transporters, for ornithine and citrulline (ORNTI) [2] and aspartate (citrin) [3] are also critical to the process. The waste nitrogen for this cycle is generated by the metabolism, primarily of amino acids, either ingested in the diet or released as the result of endogenous protein catabolism [1]. The liver is the only organ in the body to contain all of the enzymes needed for the function of the urea cycle.
Defects of all six steps of the urea cycle are known [1]. All may result in defective function of the cycle and in the accumulation of excess ammonia in the body, either continuously or intermittently, with resulting neurological damage, developmental delay, and mental retardation. Defects in any of the first five steps of the cycle have been reported to cause acute neonatal or acute intermittent hyperammonemia.
Hyperammonemia has infrequently been associated with arginase deficiency and presentation in the neonatal period is an uncommon event [4]. Ornithine transcarbamylase deficiency has the highest incidence of the six disorders and arginase and NAGS deficiencies have the lowest incidence. This is ascertained from the number and timing of the case reports, from a fairly comprehensive survey of urea cycle disorders in Japan [5] and from the screening of at least 7000 developmentally handicapped individuals in an institution for the mentally retarded in which no cases of arginase deficiency were ascertained [6]. The true incidence of arginase and NAGS deficiencies is unknown.
The first case of arginase deficiency was probably reported in 1965 by Peralta Serrano [7], but no comprehensive evaluation or enzymatic assay was done. The first family known to have this disorder was reported by Terheggen and associates in 1969 [10], [11], [12], [13]. Subsequently, more than 30 cases have been reported in the literature and a larger number are known to our metabolic team and to DeDeyn et al. [8] who published a review in the proceedings of a conference on guanidino compounds, held in Montreal in 1994. The summary material in this article derives from our own extensive experience and the collective experience reflected in that article, encompassing professor DeDeyn’s remarkable feat of having visited the majority of known patients in the world prior to that time. The disorder is inherited in an autosomal recessive manner with frequent instances of consanguinity. A pocket of increased frequency may occur amongst the French Canadian due to a well known bottleneck in the founder population of the lake region of northern Quebec province [9].
The gene for liver arginase, designated AI, was cloned in 1986 by Mori and co-workers [10] and ourselves [11], [12] and we have subsequently defined a number of natural mutations in the gene [12], [13], [14]. Ash and co-workers [15] have crystallized rat liver arginase and have super-imposed the homologous human enzyme on the coordinates derived from the rat. In addition, the perturbation in protein structure and function caused by these mutations has been described [16]. Unlike the other urea cycle enzymes, a second gene encoding arginase, with similar structural properties and enzyme characteristics, exists and has been named Arginase II (AII) [17], [18], [19], [20]. Arginase II is most abundantly expressed in kidney and prostate and is located in the mitochondrial matrix. It appears to be induced in AI deficiency and may mitigate the degree of hyperargininemia and hyperammonemia in this disease [21]. The function of AII is not well-defined or proven and is subject of intense study.
Section snippets
Clinical presentations and course
The patients whom we have seen represent the full spectrum of presentations. Thus we have chosen to report them as individuals.
Patient 1, now 13 years, was diagnosed at 4 years of age after presenting with growth failure starting at 2 years, gait abnormalities since 3 years, bilateral lower extremity spasticity, and a seizure disorder. Physical examination on presentation showed growth failure, decreased range of motion, increased tone, and extreme hyperreflexia of the lower extremities. The
Clinical characteristics
Both clinical case reports and the comprehensive examination by us and Dr. DeDeyn confirm a strikingly uniform clinical picture and one remarkably different from patients with other urea cycle disorders [4]. The condition rarely presents in the neonatal period and most patients are described as normal, or at the outer limits of normal, in early life. The first symptoms are often noted between 2 and 4 years of age and consist of clumsiness, tripping, falling, and diminished growth. If untreated,
Biochemical characteristics
The first patients were ascertained at a time when plasma amino acid determinations were more difficult and the first findings frequently were a urine amino acid pattern reminiscent of cystinuria, due to an overflow of the dibasic amino acids which shared a common kidney transport system [22], [24], [27], [28], [29], [30]. Today, plasma amino acid determination in individuals with developmental delay or neurological difficulties would reveal an elevated level of arginine [24]. If the patients
Arginase activity in arginase AI deficient patients
Arginase activity is very low or absent in the red blood cells of all patients in whom it was tested. White blood cell arginase, and in one instance stratum corneum, enzyme levels were similarly diagnostic [24]. Arginase activity in the liver has been reported in a smaller number of patients. In each, it was reduced to 10% of normal or less [21], [24], [35], [36], [37]. This accords with independent enzymological and immunological studies suggesting substantial correlation between red blood
Pathology and pathogenesis of neurological disease
Liver biopsy during acute episodes has shown swollen hepatocytes without obvious abnormalities of lipid accumulation, mitochondrial derangement or biliary defects. This is consistent with the tendency of ammonia to cause hydropic and reversible changes in hepatocytes [37]. In a number of patients, chronic fibrosis and cirrhosis were seen. As noted previously, some of patients have had abnormalities of liver function consistent with the ongoing and permanent hepatic damage, whereas the elevated
Molecular studies
Uchino et al. [12] and Vockley et al. [13], [14] have carried out mutation analysis in patients with arginase I deficiency. Nonsense mutations and small deletions were found in a large minority of the patients and were scattered randomly throughout the coding sequences. In contrast, the missense mutations were found exclusively in those residues that have been conserved in evolution and imply a critical role for these amino acids in the stability of catalytic function. Uchino et al. concluded
Treatment
Hyperargininemia is a favorable candidate for standard urea cycle therapy; limitation of natural protein intake, essential amino acid supplementation, and ammonia diversion to salvage pathways (Table 4) [20]. Arginase deficient patients are less prone to acute, uncontrolled hyperammonemia and may have no or only moderate levels of ammonia elevation on a diet containing natural foods. For those patients and families able to comply with the onerous regimen, treatment has been encouraging. At
Prenatal diagnosis and newborn screening
The arginase AI gene is located at 6q23 and arginase deficiency is inherited as an autosomal recessive disorder [44]. The recurrence risk in subsequent births to the same parents is 25%. If the mutation(s) in the patient is known, prenatal diagnosis can be accomplished by mutation analysis in chorionic villous tissue or in amniotic fluid cells. Some years ago we demonstrated that AI is expressed in fetal red cells at 16–20 weeks of gestation and at levels comparable, albeit somewhat lower than
Summary
Hyperargininemia due to liver arginase deficiency is a treatable inborn error of the urea cycle. With adherence to the dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. It appears that this favorable outcome is due, in part, to the augmented expression of a second arginase gene. The existence of this second locus provides a unique approach to treatment, if only expression could be greatly
Acknowledgments
This work was supported by the Mental Retardation Research Program in the NPI at UCLA and by USPHS Grants HD-06576, HD-31564, and HD-04612. Support for this research was also provided by Grant U54-RR019453-01 from the National Institute of Heath, Office of Rare Diseases in collaboration with the National Center for Research Resources through the Rare Disease Clinical Research Center for Inborn Errors of Urea Synthesis and Related Disorders. The authors acknowledge the encouragement and
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