ATIC – AICA-ribosiduria

AICA-ribosiduria is a rare autosomal recessive disorder caused by pathogenic variants in ATIC (HGNC:794) encoding the bifunctional purine biosynthesis enzyme PURH. Affected individuals accumulate 5-amino-4-imidazolecarboxamide (AICA) intermediates due to impaired formyl-transferase or cyclohydrolase activities, leading to a syndromic presentation with neurodevelopmental delay and multisystem involvement.

Genetic evidence includes two siblings from a consanguineous family harboring novel compound heterozygous variants c.421C>T (p.Arg141Ter) and c.1753A>G (p.Thr585Ala) resulting in a mild phenotype (2 probands, 1 family) (PMID:36367252), and three additional unrelated probands from two families carrying LoF and missense alleles, including c.1654A>T (p.Lys552Ter) (3 probands, 2 families) (PMID:32557644). All variants segregate with disease in available relatives.

The inheritance mode is autosomal recessive. Across five probands from three families, biallelic LoF (n = 2) and missense (n = 3) variants were identified by exome or targeted sequencing, with segregation confirmed in two families. The recurrent variant c.1654A>T (p.Lys552Ter) has been observed in one kindred (PMID:32557644).

Clinically, AICA-ribosiduria manifests with coarse facial features (HP:0000280), postnatal growth retardation, global psychomotor delay, progressive visual impairment, and skeletal abnormalities. Less frequent findings include aortic coarctation (HP:0001680) and nephrocalcinosis (HP:0000121). Phenotypic variability correlates with the specific domain affected (transformylase vs cyclohydrolase).

Functional assays demonstrate elevated urinary AICA-riboside levels in all subjects, confirming disrupted purine biosynthesis (PMID:36367252, PMID:32557644). Comparative enzymology suggests that transformylase-deficient alleles yield a more severe phenotype than isolated cyclohydrolase defects.

No conflicting reports have been identified to date. Integration of genetic, segregation, and biochemical data supports a strong gene–disease relationship.

Key take-home: Biallelic ATIC variants cause AICA-ribosiduria with consistent biochemical hallmarks; ATIC sequencing and urine AICA profiling are recommended for early diagnosis in patients with neurodevelopmental and facial dysmorphism.

References

• American journal of medical genetics. Part A • 2023 • Expanding the spectrum of clinical severity of AICA-ribosiduria: Report of two siblings with mild phenotype caused by a novel pathogenic variant in ATIC gene. PMID:36367252
• Journal of inherited metabolic disease • 2020 • AICA-ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long-term update on the first case. PMID:32557644

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