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

Abstract

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.

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

“…(Arg385Cys)p. (Arg385Cys)Early onsetPrenatal diagnosis ( n  = 3, Keskinen et al 2008; Balmer et al 2014), early onset ( n  = 4, this study, Kleijer et al 2002; Keskinen et al 2008), late onset ( n  = 7, Kleijer et al 2002; Keskinen et al 2008), unknown ( n  = 3, Balmer et al 2014)19c.1284G>Ac.1366C>Tp. (Trp428 * )p.…”

“…The homozygous mutation c.1153C>T p.(Arg385Cys) has been associated previously with both early-onset ( n  = 4) (Kleijer et al 2002; Keskinen et al 2008) or late-onset phenotypes ( n  = 7) (Kleijer et al 2002; Keskinen et al 2008). However, all patients with late-onset phenotype were diagnosed before 20 months of life.…”

Automated GC–MS analysis of free amino acids in biological fluids

“…Argininosuccinic aciduria is an inborn error with a urea cycle defect that causes Table 7 Serum amino acid concentrations (M) for patients with inborn errors of metabolism Table 8 Urinary amino acid concentrations (M) for patients with inborn errors of metabolism ammonia to accumulate in the blood. It is caused by a deficiency of argininosuccinate lyase [36,37]. There were no characteristic concentration changes for any of the amino acids quantified by GC-MS in the argininosuccinic aciduria-positive urine.…”

Functional Complementation in Yeast Allows Molecular Characterization of Missense Argininosuccinate Lyase Mutations

“…The disease displays clinical heterogeneity with two main clinical phenotypes: the acute/neonatal onset form, with symptoms rapidly progressing to deep coma, apnea, and death (1), and the subacute/late onset type, which is diagnosed in infancy or childhood (4). Such patients may present simply with mental retardation or an epileptic disorder.…”