AICA-ribosiduria (OMIM 608688), also known as ATIC deficiency, is an ultra-rare autosomal recessive disorder of de novo purine synthesis. It is caused by biallelic pathogenic variants in the ATIC gene. Fewer than ten confirmed patients have so far been described in peer-reviewed clinical reports.
ATIC encodes the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase, which catalyses the final two reactions of de novo purine synthesis:
AICAR → FAICAR → IMP
Impaired ATIC activity causes accumulation of AICA-riboside (AICAr), which is excreted in urine and plasma and represents the characteristic biochemical marker of the disease. SAICAr and SAdo also accumulate but in much lower levels.
Studies in patient fibroblasts and CRISPR/Cas9 cellular models have also shown that ATIC deficiency disturbs formation of the purinosome, the dynamic multienzyme complex that organizes de novo purine synthesis.
Clinical spectrum
The first patient, reported in 2004, had a severe neurological and multisystem disorder. Subsequent reports confirmed a characteristic severe phenotype but also identified more mildly affected individuals.
Frequently reported symptoms in the more severe form include:
- severe-to-profound global developmental impairment and intellectual disability;
- hypotonia;
- early-onset epilepsy, which may be difficult to control;
- severe visual impairment caused mainly by chorioretinal atrophy, sometimes described as congenital blindness;
- prenatal and postnatal growth impairment;
- progressive, often severe scoliosis;
- dysmorphic features, particularly coarse facial appearance in infancy, a prominent forehead and an upturned or broad nasal tip.
Two siblings reported in 2023 demonstrated a substantially milder phenotype. They developed psychomotor delay from the second year of life, postnatal growth impairment, progressive visual loss and mild liver dysfunction.
Diagnosis
Today, most patients are expected to be identified by exome or genome sequencing. The molecular finding should be followed by biochemical confirmation.
The principal diagnostic findings are:
- biallelic pathogenic or likely pathogenic variants in ATIC;
- markedly increased AICA-riboside in urine;
- reduced ATIC activity, where functional testing is available.
Treatment
There is currently no approved disease-modifying treatment. Clinical care is supportive and should be individualised. It may include treatment of epilepsy, ophthalmological assessment, developmental and rehabilitation therapies, nutritional and growth monitoring, orthopaedic surveillance for scoliosis and hip abnormalities, and monitoring of hepatic, renal and cardiac involvement.
A 2024 single-patient study reported that a purine-enriched diet reduced urinary excretion of AICA-riboside and succinyladenosine. The rationale is that an increased extracellular purine supply promotes salvage and suppresses de novo purine synthesis, thereby reducing production of metabolites upstream of the ATIC block. This is an important proof of principle, but clinical benefit and long-term safety have not yet been established.
As of September 2026, the PURICA study is recruiting patients to investigate purine supplementation in ATIC deficiency (ClinicalTrials.gov: NCT06845501).
Literature
all ATIC-deficiency publications in PubMed