Journal of Inherited Metabolic Disease

, Volume 25, Issue 5, pp 399–410

Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families


    • Department of Clinical GeneticsErasmus Medical Centre
  • V. H. Garritsen
    • Department of Clinical GeneticsErasmus Medical Centre
  • M. Linnebank
    • Department of PediatricsUniversity Hospital
  • P. Mooyer
    • Laboratory of Genetic Metabolic DiseasesAcademic Medical Center
  • J. G. M. Huijmans
    • Department of Clinical GeneticsErasmus Medical Centre
  • A. Mustonen
    • Department of Clinical GeneticsUniversity Hospital
  • K. O. J. Simola
    • Department of Clinical GeneticsUniversity Hospital
  • M. Arslan-Kirchner
    • Department of Human GeneticsUniversity of Hannover
  • R. Battini
    • Division of Child Neurology and PsychiatryIRCCS Stella Maris and University of Pisa
  • P. Briones
    • Instituto de Bioquimica ClinicaCorporació Sanitària y CSIC
  • E. Cardo
    • Hospital de Son Llatzer
  • H. Mandel
    • Department of PediatricsRambam Medical Center
  • E. Tschiedel
    • Department of PediatricsUniversity Hospital
  • R. J. A. Wanders
    • Laboratory of Genetic Metabolic DiseasesAcademic Medical Center
  • H. G. Koch
    • Department of PediatricsUniversity Hospital

DOI: 10.1023/A:1020108002877

Cite this article as:
Kleijer, W.J., Garritsen, V.H., Linnebank, M. et al. J Inherit Metab Dis (2002) 25: 399. doi:10.1023/A:1020108002877


A biochemical variant of argininosuccinate lyase deficiency, found in five individuals, is introduced. In comparison to classical patients, the variant cases of argininosuccinate lyase deficiency were characterized by residual enzyme activity as measured by the incorporation of [14C]citrulline into proteins. The five 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. [14C]Citrulline incorporation into proteins, which is completely blocked in classical argininosuccinic aciduria, was only partially reduced in fibroblasts of these patients. Further investigation showed that previous standard conditions of the assay were not optimal. Higher concentrations of citrulline in the incubation medium strongly stimulated 14C incorporation in normal cells, but not in the patients; as a result, the relative incorporation level in the patients dropped to 6–28% compared to 18–75% of normal in the original procedure. Prenatal diagnosis was successfully performed in three of the families. Affected pregnancies were indicated by (partial) deficiency of [14C]citrulline incorporation in chorionic villi and/or increased levels of argininosuccinate in amniotic fluid. Analysis of the ASL gene in the five patients revealed a considerable allelic heterogeneity. Three novel mutations—R385C (2 patients), V178M and R379C—were detected in homozygous states, whereas one patient was compound heterozygous for the known mutations R193Q and Q286R. In conclusion, there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical courses. In addition, we present an improved biochemical assay for accurate prenatal and postnatal diagnosis.

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© Kluwer Academic Publishers 2002