Moderate citrullinaemia without hyperammonaemia in a child with mutated and de cient argininosuccinate synthetase Wim Ruitenbeek 1 , Keiko Kobayashi 2 , Mikio Iijima 2 , Jan AM Smeitink 3 , Udo FH Engelke 1 , Ronney A De Abreu 1 , Hanneke T Kwast 1 , Takeyori Saheki 2 , Carolien A Boelen 3 , Jan GN De Jong 1 and Ron A Wevers 1 Addresses 1 Laboratory of Pediatrics & Neurology University Medical Center Nijmegen PO Box 9101 6500 HB Nijmegen The Netherlands 2 Department of Biochemistry Faculty of Medicine Kagoshima University Kagoshima Japan 3 Department of Metabolic Diseases University Medical Center Nijmegen Nijmegen The Netherlands Correspondence Dr W Ruitenbeek E-mail: [email protected] Abstract In a patient with microcephaly, feeding problems and restlessness, moderately increased serum and urine citrulline concentrations were observed. Protein and allopurinol loading did not result in additional indications for a urea cycle defect. The diagnosis of citrullinaemia was made at both the enzyme and DNA level, resulting from a novel mutation in the argininosuccinate synthetase gene. The fact that the patient has not suffered from severe deterioration, and that there were only minor abnormalities in metabolite concentrations, suggests that the argininosuccinate synthetase capacity was less affected in vivo than in vitro. In vitro nuclear magnetic resonance investigation suggested an active acetylation mechanism for citrulline. This case illustrates the importance of performing extensive biochemical and molecular investigations in order to reach a denitive diagnosis, particularly in instances of moderate citrullinaemia. Ann Clin Biochem 2003; 40: 102–107 Introduction In the majority of cases, increased concentration of citrulline in body £uids is caused by a defect in the urea cycle enzyme argininosuccinate synthetase (ASS; EC 6.3.4.5). 1 However, high serum citrulline concentrations have also been observed in some patients with argininosuccinic aciduria, sacchar- opinuria and pyruvate carboxylase de¢ciency. Argininosuccinate synthetase catalyses the generation of argininosuccinate from its substrates citrulline and aspartate in an ATP-dependent reaction in the cytosol and it forms one of the catalytic steps of the urea cycle. The gene coding for ASS in humans is located on chromosome 9q34, and the enzyme consists of four identical subunits. 1 De¢ciency of ASS usually results in hypercitrullinaemia, hyperci- trullinuria and hyperammonaemia. Orotic aciduria and hyperglutaminaemia are non-speci¢c additional abnormalities. Increased serum concentrations of citrulline, from 300 to higher than 3000 mmol/L, are found in most ASS-de¢cient patients. 1,2^4 Symptoms and age of onset vary greatly, with most patients su¡ering from mental retardation together with episodes of lethargy or coma. 1,2 The neonatal type has an often fatal course whilst the late-onset type is frequently associated only with relatively mild mental retardation. Some patients have been described with abnormalities of hair (pili torti) and skin. 5,6 The intra- familial phenotype can show great variety. 7 In addtion, asymptomatic patients with citrullinaemia have been described. 8 Patients with citrullinaemia have been classi¢ed biochemically into three groups on the basis of resi- dual ASS activity, enzyme kinetics and tissue speci¢- city of the de¢ciency. 9 Following the recent report of Kobayashi et al., 10 who identi¢ed the citrin gene responsible for adult-onset type II citrullinaemia, citrullinaemia can now be classi¢ed into classical citrullinaemia (CTLN1 type I and type III: OMIM #215700, abnormality in ASS gene) and adult-onset type II citrullinaemia (CTLN2: OMIM #603471, abnormality in SLC25A13 gene located on chromo- some 7q21.3). Type I patients with CTLN1 are char- acterized by a ubiquitous de¢ciency of ASS with abnormal kinetics of the residual ASS activity. 11^13 In 102 © 2003 The Association of Clinical Biochemists Case Report
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