Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis.

Clinical and biochemical data are presented on eight children with adenylosuccinase deficiency. This newly discovered inborn error of purine metabolism is characterized by an accumulation in body fluids of succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICA riboside), the dephosphorylated derivatives of the two substrates of adenylosuccinase. Six living children (three boys and three girls) and one deceased sibling displayed severe psychomotor retardation. Epilepsy was documented in five cases, autistic features in three, and growth retardation associated with muscular wasting in a brother and sister. In the cerebrospinal fluid, plasma and urine of these patients, the S-Ado/SAICA riboside ratio was between 1 and 2. In striking contrast, the eighth patient (a girl) was markedly less mentally retarded. Most noteworthy, the S-Ado/SAICA riboside ratio in her body fluids was around 5, suggesting that her milder psychomotor retardation was causally linked to this higher ratio. Adenylosuccinase deficiency was demonstrated in the liver of all seven living children, in the kidney of three patients in whom the enzymatic activity was measured, and in the muscle of three patients, including the two with muscular wasting. In fibroblasts of the six severely retarded patients, adenylosuccinase activity was reduced to approximately 40% of normal; in the patient with the higher S-Ado/SAICA riboside ratio, it reached only 6% of normal. The clinical heterogeneity of adenylosuccinase deficiency justifies systematic screening for the enzyme defect in unexplained neurological disease.