Disorder of urea cycle metabolism and ammonia detoxification
-Rare genetic disease
Comment:
Argininemia belongs to the class of urea cycle disorders and is caused by deficiency of the enzyme arginase (ARG1), one of the six enzymes and two transporters involved in the detoxification of ammonium to urea. First symptoms, often neurologically based, typically present in children between 2 and 4 years of age (PMID:15694174). Argininemia is often misdiagnosed as cerebral palsy (PMID:26123990).
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 ... 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.
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 ... 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.
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, ... 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.
Clinical findings are not specific, but the disorder may be suspected in instances of progressive loss of developmental milestones and spasticity. ...
DiagnosisClinical DiagnosisClinical findings are not specific, but the disorder may be suspected in instances of progressive loss of developmental milestones and spasticity. TestingPlasma arginine concentration. Elevation of plasma arginine concentration three- to fourfold above the upper limit of normal is highly suggestive of the diagnosis. Note: Up to twofold elevations may be seen in infants who do not have arginase deficiency and who are otherwise normal.Plasma ammonia concentration. Elevation of plasma ammonia concentration may be intermittent. Acute hyperammonemia (plasma ammonia concentration >150 µmol/L) is uncommon. Urinary orotic acid concentration. Urinary orotic acid concentration is often elevated but is not a primary screen for the disorder. Red blood cell arginase enzyme activity. Arginase enzyme assay can be used to confirm the diagnosis. Affected individuals. Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Arginase enzyme activity is reduced in liver as well as red blood cells, but arginase enzyme activity in liver is rarely measured because of the risks involved in liver biopsy and the ease of diagnosis from red blood cells. Carriers. The normal mean red blood cell arginase enzyme activity is 100 times the lower limit of detection. Thus, most obligate carriers have been easily distinguished from normal. However, in at least one instance, a mother who was an obligate carrier tested in the mid-normal range. Molecular Genetic TestingGene. ARG1 is the only gene in which mutations are known to cause arginase deficiency. Clinical testingSequence analysis of the ARG1 coding region has detected mutations in most affected individuals tested to date, but sample size is small and no statement about mutation detection rate can be made at this time. [J Haberle, personal communication]. Deletion/duplication analysis. Whole-gene deletion, beginning in intron 1 and including the remainder of the gene, has been reported [Korman et al 2004] Table 1. Summary of Molecular Genetic Testing Used in Arginase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityARG1Sequence analysisSequence variants 2UnknownClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice-site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandPlasma arginine elevation is the primary means of ascertainment. Until recently, red blood cell enzyme testing was the gold standard for diagnostic confirmation. Molecular genetic testing (sequence analysis followed by deletion/duplication analysis if two mutations are not identified) is now readily available and is an alternative to enzyme testing as the first-line confirmatory test. Enzyme assay remains the norm if two mutations are not found. The degree of enzyme deficiency in red blood cells or the genotype cannot be used to establish disease severity or prognosis as they are but two of several factors involved in the outcome.Carrier testing for at-risk relatives using molecular genetic testing requires prior identification of the disease-causing ARG1 mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies using molecular genetic testing require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in ARG1.
Unlike any of the other eight primary urea cycle disorders (see Urea Cycle Disorders Overview), arginase deficiency rarely results in elevated plasma ammonia concentration in the newborn period, even in individuals with two null mutations. Episodic hyperammonemia of variable degree may occur but is rarely severe enough to be life threatening or to cause death. Hyperammonemia is often recognized only if blood ammonia or plasma amino acid concentrations are obtained during an acute illness. Although data are not available, it appears that more than 75% of affected individuals survive their disease and live long, albeit handicapped lives. ...
Natural HistoryUnlike any of the other eight primary urea cycle disorders (see Urea Cycle Disorders Overview), arginase deficiency rarely results in elevated plasma ammonia concentration in the newborn period, even in individuals with two null mutations. Episodic hyperammonemia of variable degree may occur but is rarely severe enough to be life threatening or to cause death. Hyperammonemia is often recognized only if blood ammonia or plasma amino acid concentrations are obtained during an acute illness. Although data are not available, it appears that more than 75% of affected individuals survive their disease and live long, albeit handicapped lives. Most commonly, birth and early childhood are normal. At the age of one to three years, linear growth slows and spasticity, more commonly spastic diplegia, begins to develop. Soon, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability.Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures.All affected individuals have growth deficiency.Seizures are common and are usually controlled easily.Other parts of the nervous system including basal ganglia, cerebellum, medulla, and spinal cord are largely spared [De Deyn et al 1997].Older individuals may present with postoperative encephalopathy.
Hyperammonemia. Arginase is the sixth and final enzyme of the eight known steps in the urea cycle. See Urea Cycle Disorders Overview for approaches to distinguish: (1) other causes of hyperammonemia from a urea cycle disorder and (2) the differences between the urea cycle disorders themselves. ...
Differential DiagnosisHyperammonemia. Arginase is the sixth and final enzyme of the eight known steps in the urea cycle. See Urea Cycle Disorders Overview for approaches to distinguish: (1) other causes of hyperammonemia from a urea cycle disorder and (2) the differences between the urea cycle disorders themselves. Spasticity. Arginase deficiency may be misdiagnosed as static spastic diplegia (cerebral palsy). See Hereditary Spastic Paraplegia Overview. It should be noted that arginase deficiency is one of the few treatable causes of spastic diplegia [Prasad et al 1997]. ARG2. A second arginase gene is known (ARG2), but no human deficiency state has been identified and it is not clear that elevated plasma arginine would be a part of such a deficiency. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with arginase deficiency, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with arginase deficiency, the following evaluations are recommended:Plasma ammonia concentration Plasma arginine concentration Developmental assessment Complete neurologic evaluation Genetics consultationTreatment of ManifestationsThe management of individuals with arginase deficiency should closely mirror that described in the Urea Cycle Disorders Overview, with one caveat: individuals with arginase deficiency are less prone to episodes of hyperammonemia and when present, hyperammonemia is more likely to respond to conservative management such as intravenous fluid administration. However, the individual who is comatose and encephalopathic is at high risk for severe brain damage and should be treated accordingly. Arginine supplementation is obviously contraindicated. Infants should be managed by a team coordinated by a metabolic specialist in a specialized center. In the acute phase, the mainstays of treatment are the following: Rapidly reducing plasma ammonia concentration. The best way to reduce plasma ammonia concentration quickly is by dialysis; the faster the flow rate of dialysate, the faster the clearance of ammonia from the plasma. The method employed depends on the affected individual's circumstances and available resources. Fastest is use of pump-driven dialysis, in which an extracorporeal membrane oxygenation (ECMO) pump is used to drive a hemodialysis (HD) machine. Other methods are hemofiltration (both arteriovenous and venovenous), peritoneal dialysis, and continuous-drainage peritoneal dialysis. Dialysis can usually be discontinued when plasma ammonia concentration falls below 200 µmol/L. Affected individuals often experience a "rebound" hyperammonemia that may require further dialysis, although rarely is this level of intervention required in arginase deficiency. Pharmacologic management to allow alternative pathway excretion of excess nitrogen. Blocking the production of ammonia and the need for ureagenesis is accomplished by diminishing catabolism with adequate non-protein calories and with a combination of the nitrogen scavenger drugs sodium phenylacetate and sodium benzoate. A loading dose of the drugs is followed by maintenance administration, initially intravenously and later orally when the individual is stable. Intravenous forms of these medications are now approved by the FDA and are generally available. Reducing the amount of excess nitrogen in the diet and reducing catabolism through the introduction of calories supplied by carbohydrates and fat. In acutely ill individuals, calories should be provided as carbohydrate and fat, either intravenously as glucose and Intralipid® or orally as protein-free oral formula, such as Mead Johnson 80056® or Ross Formula ProPhree®; however, complete restriction of protein should not exceed 24-48 hours, because depletion of essential amino acids may result in endogenous protein catabolism and nitrogen release. High parenteral glucose plus insulin can be used acutely to diminish endogenous protein catabolism. Individuals should be transitioned from parenteral to enteral feeds as soon as possible. In early treatment, feeding 1.0 to 1.5 g of protein/kg body weight with 50% as essential amino acids is advised, particularly for infants. Older children require and tolerate lower protein intake. Reducing the risk of neurologic damage. Cautionary measures are physiologic stabilization with intravenous fluids (10% dextrose with one-quarter normal saline) and cardiac pressors as necessary while avoiding overhydration and resulting cerebral edema, the duration of which correlates with poor neurologic outcome. Older individuals are at risk for episodes of hyperammonemia and should continue to be managed by a specialist in metabolic disorders. Seizures are easily treated by phenobarbital or carbamazepine. Acute intercurrent illnesses should be treated promptly with special dietary intervention or hospitalization to minimize the effect of catabolism. Prevention of Primary ManifestationsThe goal should be maintenance of plasma arginine concentration as near normal as possible, consistent with the individual's tolerance for the following interventions:Restriction of dietary protein through use of specialized formulas. In the best of circumstances, the affected individual should be on the minimal protein intake needed to maintain protein biosynthetic function, growth, and normal or near-normal plasma amino acid concentrations. Half or more of dietary protein should be an arginine-free essential amino acid mixture. Administration of oral nitrogen scavenging drugs. Sodium benzoate or sodium phenylbutyrate at a dose of 250 mg/kg/day up to 10 g/day (typically described as per meter sq body surface area) in three divided doses may be used as well [De Deyn et al 1997, Iyer et al 1998]. Liver transplantation eliminates the hyperargininemia and presumably the risk for hyperammonemia.Prevention of Secondary ComplicationsMost individuals with arginase deficiency have persistent hepatic synthetic function abnormalities, particularly, elevated prothrombin time. In some circumstances hepatic fibrosis and cirrhosis have developed and have either been fatal or required a liver transplant. Arginine is the substrate for nitric oxide synthase; however, abnormalities in this pathway have not been described. The spasticity may be reactive and instances of marked improvement with Botox® have been described.SurveillancePatients are seen at regular intervals determined by their age and degree of metabolic stability. Infants should be seen monthly or more frequently, with monitoring of plasma concentration of ammonia and amino acids, growth, and neurologic function. If treatment fails to arrest the neurologic deterioration or if spasticity is symptomatic, appropriate orthopedic and physical therapy interventions are indicated.Agents/Circumstances to AvoidValproic acid is to be avoided as it exacerbates hyperammonemia in urea cycle and other inborn errors of metabolism [Scaglia & Lee 2006]. Evaluation of Relatives at RiskBecause the age of onset is delayed and the manifestations can vary, all sibs, but especially younger ones, should be tested by plasma quantitative amino acid analysis or by enzymatic and/or molecular genetic testing if the family-specific mutations are known to see if they are affected so that morbidity can be reduced by early diagnosis and treatment. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementThe authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency; therefore, no inference can be drawn about the safety of pregnancy to the mother or the fetus. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherImmunizations can be provided on the usual schedule. Multivitamin and fluoride supplementation are indicated for all affected individuals.Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Arginase Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDARG16q23.2Arginase-1ARG1 @ LOVDARG1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Arginase Deficiency (View All in OMIM) View in own window 207800ARGININEMIA 608313ARGINASE, LIVER; ARG1Normal allelic variants. ARG1 is approximately 10-15 kb in length and comprises eight exons and seven introns (see Ensembl Gene Report). Pathologic allelic variants. Mutations are located throughout the coding region of the gene. Missense mutations are generally found in amino acids that have been highly conserved during evolution and especially in sequences involved in the active site of the enzyme. Chain-terminating mutations and deletions and insertions may be found anywhere in the gene [Vockley et al 1996]. A deletion of nearly the entire gene has also been described [Korman et al 2004].Normal gene product. Arginase-1 is 322 amino acids long and is manganese dependent; it exists in nature as a trimer, and, unlike arginase-2, which is located in mitochondrial matrix, is located in the cytosol. The enzyme is highly stable and can be completely reactivated, if not denatured, by treating with manganese at 65° C. Expression is highest in the liver and RBCs (Reference sequence NP_000036.2).Abnormal gene product. The mutated arginase-1 protein is rarely stable enough to be detected in the mature red blood cells of affected individuals by immunologic means. A second, ancestral arginase gene (ARG2) located on 14q, is expressed in different tissue and cell types and may partially compensate for deficiency of arginase-1. It is thought that from an evolutionary perspective, ARG2 existed first and that ARG1 arose from it following a gene duplication event. The two gene products are more than 50% homologous at the amino acid level [Morris et al 1997, Iyer et al 1998].