Abstract
Argininosuccinate lyase (ASL) deficiency (McKusick 207900) is an inborn error of the urea cycle. The leading symptom is progressive hyperammonaemia, which is a life-threatening condition, particularly in patients with a neonatal onset. Early diagnosis and treatment of the hyperammonaemia are necessary to improve survival and the long-term outcome of ASL-deficient patients. Currently, the diagnosis of ASL deficiency is based on the measurement of urea cycle intermediates and amino acids by automated quantitative ion exchange chromatography in plasma and urine. Here, we report a newborn presenting with coma and severe hyperammonaemia. ASL deficiency was suspected on the basis of an adapted tandem mass spectrometric (MS-MS) procedure which allows determination of argininosuccinate in addition to the amino acids in serum samples. MS-MS measurements revealed a characteristic increase of argininosuccinate, a moderate increase of citrulline, and lowered levels of arginine and ornithine in the serum of the patient. The diagnosis was confirmed by the detection of a novel homozygous frameshift mutation in exon 14 of the argininosuccinate lyase gene. We propose MS-MS as a diagnostic tool suitable for the rapid detection of specific alterations in the amino acid spectra caused by ASL deficiency.
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REFERENCES
Barbosa P, Cialkowski M, O'Brien WE (1991) Analysis of naturally occurring and site-directed mutations in the argininosuccinate lyase gene. J Biol Chem 266: 5286-5290.
Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. J Clin Invest 74: 2144-2148.
Brusilow SW, Horwich AL (1995) Urea cycle enzymes. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, vol. 1. New York: McGraw-Hill, 1187-1232.
Casetta B, Tagliacozzi D, Shushan B, et al (2000) Development of a method for rapid quantitation of amino acids by liquid chromatography-tandem mass spectrometry (LC-MSMS) in plasma. Clin Chem Lab Med 38: 391-401.
Feillet F, Leonard JV (1998) Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 21: 101-111.
Gempel K, Kottlors M, Jaksch M, et al (1999) Adult carnitine palmitoyltransferase II deficiency: detection of characteristic carnitine esters in serum by tandem mass spectrometry. J Inherit Metab Dis 22: 941-942.
Howell PL, Turner MA, Christodoulou J, et al (1998) Intragenic complementation at the argininosuccinate lyase locus: reconstruction of the active site. J Inherit Metab Dis 21: 72-85.
Ito T, van Kuilenburg AB, Bootsma AH, et al (2000) Rapid screening of high-risk patients for disorders of purine and pyrimidine metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or urine-soaked filter paper strips. Clin Chem 46: 445-452.
Linnebank M, Homberger A, Rapp B, et al (2000) Two novel mutations (E86A, R113W) in argininosuccinate lyase deficiency and evidence for highly variable splicing of the human argininosuccinate lyase gene. J Inherit Metab Dis 23: 308-312.
Matuo S, Tatsuno M, Kobayashi K, et al (1988) Isolation of cDNA clones of human argininosuccinate lyase and corrected amino acid sequence. FEBS Lett 234: 395-399.
McInnes RR, Shih V, Chilton S (1984) Interallelic complementation in an inborn error of metabolism: genetic heterogeneity in argininosuccinate lyase deficiency. Proc Natl Acad Sci USA 81: 4480-4484.
Msall M, Batshaw ML, Suss R, et al (1984) Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 310: 1500-1505.
O'Brien WE, McInnes R, Kalumuck K, et al (1986) Clining and sequence analysis of cDNA for human argininosuccinate lyase. Proc Natl Acad Sci USA 83: 7211-7215.
Rashed MS, Ozand PT, Bucknall MP, et al (1995) Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 38: 324-331.
Schwarz S, Schwab S, Hoffmann GF (1999) Enzyme defects of the urea cycle in differential acute encephalopathy diagnosis in adulthood. Diagnosis and current therapy concepts. Nervenarzt 70: 111-118.
Todd S, McGill JR, McCombs JL, et al (1989) cDNA sequence, interspecies comparison, and gene mapping analysis of argininosuccinate lyase. Genomics 4: 53-59.
Turner MA, Simpson A, McInnes RR, et al (1997) Human argininosuccinate lyase: a structural basis for intragenic complementation. Proc Natl Acad Sci USA 94: 9063-9068.
Walker DC, McCloskey DA, Simard LR, et al (1990) Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc Natl Acad Sci USA 87: 9625-9629.
Yu B, Howell PL (2000) Intragenic complementation and the structure and function of argininosuccinate lyase. Cell Mol Life Sci 57: 1637-1651.
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Stadler, S., Gempel, K., Bieger, I. et al. Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry. J Inherit Metab Dis 24, 370–378 (2001). https://doi.org/10.1023/A:1010560704092
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DOI: https://doi.org/10.1023/A:1010560704092