#207800
ICD+
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| ARGININEMIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| ARGINASE DEFICIENCY HYPERARGININEMIA ARG1 DEFICIENCY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because argininemia is caused by mutation in the gene encoding liver arginase (ARG1; 608313). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arginase deficiency is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle, the hydrolysis of arginine to urea and ornithine. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Terheggen et al. (1969, 1970) described 2 sisters, aged 18 months and 5 years, with spastic paraplegia, epileptic seizures, and severe mental retardation. The parents were related. Arginine levels were high in the blood and spinal fluid of the patients, with intermediate elevations in both parents and in 2 healthy sibs. Arginase activity in red cells was very low in the patients and intermediate in the parents. In 1971 another affected girl was born into the family observed by Terheggen et al. (1972, 1975). There was late introduction of a low protein diet, but the infant developed severe mental retardation, athetosis, and spasticity. Cederbaum et al. (1977) reported a 7.5-year-old boy with progressive psychomotor retardation, behavior disturbance, and spasticity, who had growth arrest from age 3 years. Plasma arginine was increased, and red blood cell arginase activity was less than 1% of normal, whereas it was half-normal in both parents, 2 unaffected sibs, and in his paternal grandfather. Cederbaum et al. (1977) concluded that arginase deficiency is an autosomal recessive disorder. Michels and Beaudet (1978) reported an affected Mexican child with growth retardation, microcephaly, mental retardation, spasticity, and epileptiform discharges on EEG. In the province of Quebec, Qureshi et al. (1983) identified an affected French-Canadian family. Both parents showed activity of arginase 32 to 38% of normal. Walser (1983) stated that only 8 kindreds (with 13 patients) had been reported and that 4 of these (with 7 patients) were Spanish or Spanish-American. Jorda et al. (1986) described an unusually severe case of arginase deficiency in a Spanish infant who showed marked protein intolerance early in life. The levels of red cell arginase in the parents and 1 sister were consistent with heterozygosity. Brockstedt et al. (1990) described argininemia in a 4-year-old boy born of consanguineous Pakistani parents. He had microcephaly and spastic tetraplegia. Pregnancy and birth were uneventful and psychomotor development during the first 2 years of life were presumably normal. Vilarinho et al. (1990) described argininemia in a 5-year-old Portuguese boy who did not show spastic diplegia. His first manifestation, at 3.5 years of age, was a partial seizure for 15 minutes without loss of consciousness. Six months later he showed the same clinical features over a period of 15 days. The electroencephalogram showed partial left temporal and paracentral spikes. At 4.5 years of age he began to have episodes of vomiting, hypotonia, irritability, and ataxia. In a patient dying with severe argininemia, Grody et al. (1989) demonstrated total absence of arginase I in tissues, whereas arginase II was increased about 4-fold in kidney. The patient, an offspring of first-cousin parents of Cambodian descent, died at 6 months of age. Although Southern blot analysis failed to show a substantial deletion in the ARG1 gene, no cross-reactive arginine I protein could be demonstrated by immunoprecipitation-competition and Western blot analysis. Induction studies in cell lines that express only the type II isozyme indicated that its activity could be enhanced several fold by exposure to elevated arginine levels. This presumably was the mechanism for the high level of the enzyme in the patient and explained the fact that there is persistent ureagenesis in this disorder. Christmann et al. (1990) described a patient in whom the diagnosis of argininemia was first made at the age of 18 years when treatment with sodium valproate was initiated for seizures. The patient had psychomotor regression since the age of 15 months with paraparesis since she was 3 years old. By the age of 18, she was bedridden. Five days after the initiation of valproate therapy, she went into a state of stupor and was found to have marked hyperammonemia. 'Valproate sensitivity' has been observed also with ornithine transcarbamylase deficiency and citrullinemia, 2 other causes of hyperammonemia. Scheuerle et al. (1993) described 2 unrelated patients, aged 9 and 5 years, who had been thought to have cerebral palsy and were later found to have arginase deficiency. The experience suggested that the condition may be underdiagnosed because of its relatively mild symptoms. The authors noted that arginase deficiency does not commonly have the severe hyperammonemia seen with other urea cycle disorders. Cowley et al. (1998) described an 18-year-old woman, born of related parents, who had been well as a child with normal growth and development. She presented for investigation of collapse with sudden onset of spastic diplegia. She had mild, tender hepatomegaly. Over the previous 6 months, she had been ill with episodic nausea and vomiting, and had experienced some degree of lower limb weakness over the previous 2 weeks. The spastic diplegia in this patient was considered stereotypical of arginase deficiency. No arginase activity was detected in liver tissue; red cell arginase activity was low normal. Picker et al. (2003) described a rare neonatal and fatal presentation of arginase deficiency in a 2-day-old female with markedly elevated plasma arginine, lactate, and CSF glutamine, and modestly elevated blood ammonia, who developed hypertonia and tachypnea followed by intractable seizures and global cerebral edema. The infant also had an atypical presence of the ARG2 isozyme (107830) in the liver. Picker et al. (2003) suggested that the cerebral edema and the fatal course, both of which have been reported in older patients, were due to the increased intracellular osmolarity of the elevated glutamine. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Qureshi et al. (1984) recommended a combination of benzoate with arginine restriction in the management of hyperargininemia. Bernar et al. (1986) reported the case of a 12-year-old boy with less marked elevations of plasma arginine and less severe intellectual impairment. Both were attributed to a self-selected low-protein diet. Therapy with sodium benzoate and dietary restriction caused an impressive improvement. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a study of 20 persons homozygous or heterozygous for arginase deficiency, Grody et al. (1989) found no substantial structural ARG1 gene deletions or other rearrangements by Southern blot analysis. In a Japanese girl with argininemia, Haraguchi et al. (1990) found compound heterozygosity for 2 frameshift deletions in the ARG1 gene (608313.0001-608313.0002). In 11 patients with argininemia, 9 separate mutations representing 21 of the 22 mutant alleles were identified by Uchino et al. (1995) (see, e.g., 608313.0008-608313.0011). Four of these mutations, accounting for 64% of the mutant alleles, were expressed in vitro and were found to be severe or moderate. Patients with at least one 'moderate' mutant allele responded well to dietary treatment, whereas patients with 2 'severe' alleles did not respond to dietary treatment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Shih et al. (1972) found high blood arginine levels and low red cell arginase in Macaca fascicularis monkeys in the New England Regional Primate Center, indicating arginase deficiency. Iyer et al. (2002) produced Arg1-knockout mice that duplicated several pathobiologic aspects of human argininemia. Deignan et al. (2008) stated that several guanidino compounds, which are direct or indirect metabolites of arginine, are elevated in the blood of uremic patients and in the plasma and cerebrospinal fluid of hyperargininemic patients. They found that the guanidino compounds alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and argininic acid were increased in brain tissue from the Arg1-deficient mouse model of hyperargininemia. Several guanidino compounds were also elevated in plasma, liver, and kidney. Deignan et al. (2008) concluded that guanidino compounds may be the neuropathogenic agents responsible for complications in arginase deficiency. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The prevalence of argininemia is estimated to be 1 in 1,100,000 (Testai and Gorelick, 2010). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The observation that researchers working with the Shope virus have low blood arginine led to the use of Shope virus in the treatment of this disorder. Rogers et al. (1973) reported an induction of arginase activity by inoculation of the Shope virus into tissue cultures of an argininemic patient's fibroblasts. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Snyderman et al. (1977); Snyderman et al. (1979); Spector et al. (1980); Spector et al. (1983); Uchino et al. (1992); Van Elsen and Leroy (1977) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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