#207900
ICD+
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| ARGININOSUCCINIC ACIDURIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| ARGININOSUCCINASE DEFICIENCY ARGININOSUCCINATE LYASE DEFICIENCY ASL DEFICIENCY ARGININOSUCCINIC ACID LYASE DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because argininosuccinic aciduria is caused by mutation in the gene encoding argininosuccinate lyase (ASL; 608310). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. 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, and arginase deficiency (207800). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Two forms of argininosuccinic aciduria have been recognized: an early-onset, or malignant, type and a late-onset type. As originally described by Allan et al. (1958), onset of symptoms of argininosuccinic aciduria occurs in the first weeks of life. Features include mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red. Coryell et al. (1964) reported familial association of argininosuccinic aciduria. They noted that in the U.S., where arginine is probably supplied adequately by the usual diet, brittle hair may not occur as often as in Great Britain, where the average protein intake is less ample. Shih et al. (1969) reported deficiency of argininosuccinase in cultured fibroblasts from patients. Lewis and Miller (1970) described the neuropathologic changes in argininosuccinic aciduria. They noted that astrocyte transformation to Alzheimer type II glia may be a consistent feature of any form of hyperammonemia. Postmortem liver showed marked deficiency of argininosuccinate lyase. Asai et al. (1997) described fatal hyperammonemia in a child with argininosuccinic aciduria following enflurane anesthesia. The diagnosis of argininosuccinic aciduria had been made while the patient was hospitalized for febrile seizures at the age of 18 months. Plasma argininosuccinate was markedly elevated. Argininosuccinase activity was absent in her erythrocytes and was within the heterozygous range in both parents. Oral arginine supplementation and a low protein diet were started. At 13 years of age, the patient underwent an inguinal hernioplasty. The preoperative state was satisfactory except for hepatomegaly and mental retardation. All routine investigations were normal, including those for ammonia. During the second evening after operation, the patient became lethargic with frequent convulsions despite adequate levels of the 3 antiepileptics on which she had been maintained for many years. Despite intravenous hypertonic glucose and arginine supplementation, her ammonia level rose greatly and she became comatose. Despite repeated hemodialysis, she died on the sixth postoperative day. Hepatic findings were consistent with fatty changes. Asai et al. (1997) suggested that although it was tempting to conclude that only enflurane was directly responsible for the hyperammonemia in the patient and although this relationship was not proved beyond reasonable doubt, general anesthesia, including enflurane, should be avoided in patients with argininosuccinic aciduria. Kleijer et al. (2002) reported a biochemical variant of argininosuccinate lyase deficiency found in 5 individuals. In comparison to classic cases, the variant cases of argininosuccinate lyase deficiency were characterized by residual enzyme activity as measured by the incorporation of C-14-citrulline into proteins. The 5 patients of different ethnic backgrounds presented with relatively mild clinical symptoms, variable age of onset, marked argininosuccinic aciduria, and severe, but not complete, deficiency of argininosuccinate lyase. C14-citrulline incorporation into proteins, which is completely blocked in classic argininosuccinic aciduria, was only partially reduced in fibroblasts of these patients. All of these patients were found to have mutations in the ASL gene (see, e.g., 608310.0004-608310.0006). The authors concluded that there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical course. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Pijpers et al. (1990) established the diagnosis of argininosuccinic aciduria in both fetuses of a dizygotic pregnancy, using transabdominal chorionic villus sampling at 10 weeks' gestation. Kleijer et al. (2002) performed successful molecular prenatal diagnosis in 3 affected families. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brusilow and Batshaw (1979) reported success with arginine treatment in argininosuccinase deficiency. The treatment favors the formation of argininosuccinic acid (ASA); since ASA contains the 2 waste nitrogen atoms later excreted in urea in healthy persons, and since it has a renal clearance similar to the glomerular filtration rate, the authors reasoned that hyperammonemia might be relieved by arginine therapy, provided stoichiometric amounts of ornithine are available. Kvedar et al. (1991) observed 'normalization' of hair shafts after patients were treated with a low protein, arginine-supplemented diet. Widhalm et al. (1992) described a follow-up of 12 Austrian children detected since 1973 in a national neonate screening program. All were managed with a daily arginine supplement in conjunction with either a normal diet or a special diet in which protein intake was restricted. They found that early treatment of partial argininosuccinate lyase deficiency resulted in normal intellectual and psychomotor development. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early Identification of Complementation Groups In study of 5 cell lines from patients with argininosuccinate lyase deficiency, Cathelineau et al. (1981) observed 2 complementation groups. Since the restoration of activity was not total, the complementation was assumed to be intragenic. McInnes et al. (1984) performed complementation analysis in a search for genetic heterogeneity in this disorder. In 20 of 28 fibroblast strains cultured from patients with ASL deficiency, partial complementation was observed, with 2- to 10-fold increases in lyase activity. The data suggested that all the mutants were affected at a single locus, which the authors suggested was the structural gene coding for that enzyme. McInnes et al. (1984) presented a complementation map of the gene. The authors noted that there are few examples of interallelic complementation in human genetics: galactosemia (230400) and propionyl-CoA-carboxylase deficiency (606054) are among them. ASL is a homotetramer; in microorganisms, interallelic complementation has been found to be almost universal at loci coding for homomultimeric proteins. The same group Simard et al. (1986) found differing levels of ASL cross-reactive material (CRM) in different fibroblast lines, suggesting the presence of multiple lyase mutant monomers and mutations underlying ASL deficiency. Many of these mutants were indistinguishable by clinical, enzymatic, or complementation analysis. In 15 unrelated patients who were compound heterozygotes for mutations at the ASL locus, Linnebank et al. (2002) could find no evidence that interallelic complementation plays a major role for modifying biochemical phenotypes. Disease-Causing Mutations In a patient with ASL deficiency, born of a consanguineous mating, Walker et al. (1990) identified a homozygous mutation in the ASL gene (608310.0001). The residual activity of the mutant enzyme was about 1%. In 27 unrelated patients with ASL deficiency, Linnebank et al. (2002) identified 23 different mutations, 19 novel, in the ASL gene. Fifteen of the 54 alleles had an IVS5+1G-A splice site mutation (608310.0003). In 5 patients with a biochemical variant of ASL deficiency in which there was residual enzyme activity and mild clinical symptoms, Kleijer et al. (2002) identified several mutations in the ASL gene. R385C (608310.0004), V178M (608310.0005), and R379C (608310.0006) were detected in homozygous states, whereas 1 patient was compound heterozygous for 2 known mutations, including Q286R (608310.0002). Prenatal diagnosis was successfully performed in 3 of the families. Trevisson et al. (2007) identified 16 different mutations in the ASL gene, including 14 novel mutations, in 12 Italian patients from 10 families with ASL deficiency. All patients tested, except 1, had less than 5% residual enzyme activity. Mutations were scattered throughout the gene, but there were no genotype/phenotype correlations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The prevalence of argininosuccinic aciduria is estimated to be 1 in 150,000 (Testai and Gorelick, 2010). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bohles et al. (1978); Collins et al. (1980); Fleisher et al. (1979); Glick et al. (1976); Goodman et al. (1973); Kint and Carton (1968); Levin (1967); Levin et al. (1961); Moser et al. (1967); Qureshi et al. (1978); Van der Heiden et al. (1976) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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