A Rare Case of 5-Amino-4-Imidazolecarboxamide-Ribosiduria (AICA-Ribosiduria) Due to a Novel Biallelic ATIC Variant

Introduction: AICA-ribosiduria, a rare autosomal recessive disorder, disrupts purine biosynthesis via ATIC gene mutations. Only 8 cases from 6 families are reported. We present the oldest known case at diagnosis with a milder phenotype and novel variants. Case Description: A 36-year-old Chinese man with retinal dystrophy, severe intellectual delay, and persistent hyperuricemia was evaluated. Developmental delays were evident by age 5; vision loss began at 8. He’s of Chinese descent without history of consanguinity. He's 154.6 cm tall, weighs 52.4 kg, and he communicates using short phrases. Physical examination revealed hyperpigmentation on the right arm and interscapular region, scoliosis, MCP hyperextension, and muscle wasting. Initial whole genome sequencing (WGS) in 2019 and re-analyses in 2022–2023 were inconclusive. Re-analysis in 2024 for vision decline identified compound heterozygous ATIC variants: a pathogenic c.380-5_392del and a VUS c.1662T>G p.(Ser554Arg), both novel. Brain MRI showed right caudate gliosis and prior microhemorrhage/mineralization. EEG revealed mild diffuse slowing. Echo was normal. Labs were unremarkable except for chronic hyperuricemia. Urinalysis, renal ultrasound, and urine organic acids were normal. Discussion: AICA-ribosiduria typically presents in infancy with severe neurodevelopmental and skeletal features. Only 2 cases with milder forms were reported, both in infancy. This is the third mild case—and the oldest diagnosed—harboring novel variants. While in silico studies suggest pathogenicity of the VUS, functional studies are lacking. However, a pathogenic variant alongside a VUS altering a conserved residue in a key enzymatic domain is concerning. Hyperuricemia, not seen in prior cases, may reflect phenotypic variability. Early recognition is key for management and support.