AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC

Abstract

In a female infant with dysmorphic features, severe neurological defects, and congenital blindness, a positive urinary Bratton-Marshall test led to identification of a massive excretion of 5-amino-4-imidazolecarboxamide (AICA)-riboside, the dephosphorylated counterpart of AICAR (also termed "ZMP"), an intermediate of de novo purine biosynthesis. ZMP and its di- and triphosphate accumulated in the patient's erythrocytes. Incubation of her fibroblasts with AICA-riboside led to accumulation of AICAR, not observed in control cells, suggesting impairment of the final steps of purine biosynthesis, catalyzed by the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase (ATIC). AICAR transformylase was profoundly deficient, whereas the IMP cyclohydrolase level was 40% of normal. Sequencing of ATIC showed a K426R change in the transformylase region in one allele and a frameshift in the other. Recombinant protein carrying mutation K426R completely lacks AICAR transformylase activity.

Figure 1

Pathway of purine metabolism. 1, ADSL. 2a, AICAR-TF. 2b, IMP-CH. 3, Adenylosuccinate synthetase. 4, AMP deaminase. 5, 5′-nucleotidase. 6, Purine nucleoside phosphorylase. 7, Adenosine deaminase. 8, HGPRT. 9, APRT. 10, Adenosine kinase. 11, Xanthine oxidase.

Figure 2

HPLC of urine. Urine samples were analyzed by HPLC, with diode-array UV detection, on an Alltima C18 5u (250×246 mm) reversed-phase column (Alltech), as described elsewhere (Marie et al. 2000).