A number sign (#) is used with this entry because of evidence that AICA-ribosiduria due to ATIC deficiency is caused by homozygous or compound heterozygous mutation in the ATIC gene (601731) on chromosome 2q35.

AICA-ribosiduria is characterized by severe to profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante-postnatal growth impairment, and severe scoliosis. Dysmorphic features include coarse facies and upturned nose. Early-onset epilepsy may occur. Less common features may include aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis (Ramond et al., 2020).

Marie et al. (2004) described a 4-year-old girl who presented with a devastating neurologic picture involving profound mental retardation, epilepsy, dysmorphic features, and congenital blindness. Dysmorphic features included cutaneous dimples on the extensor side of knees, elbows, and shoulders. By age 12 months, bilateral atrophic pigmented chorioretinal macular lesions had developed with optic atrophy, and abnormal electroretinograms and visual evoked potentials were observed. Chromatograms of the patient's urine revealed 3 peaks seen neither in control individuals' urine nor in that of ADSL (608222)-deficient patients (103050). The major peak was identified as 5-amino-4-imidazolecarboxamide riboside (AICA-riboside), on the basis of a positive Bratton-Marshall test, spectral analysis, and spiking with the authentic compound. AICA-riboside is the nucleoside corresponding to AICAR (AICA-ribotide, also termed ZMP), an intermediate of the de novo purine biosynthetic pathway. AICA-riboside is formed by dephosphorylation of AICAR, most likely by IMP-GMP 5-prime-nucleotidase. When Marie et al. (2004) incubated fibroblasts from their patient with AICA-riboside, they observed 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; 601731). AICAR transformylase was profoundly deficient, whereas the IMP cyclohydrolase level was 40% of normal. The presence of massive amounts of AICA-riboside in the patient's urine and the accumulation of AICAR and its derivatives in her erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a clear indication of deficiency in the enzyme that utilizes this intermediate de novo purine biosynthesis, the bifunctional enzyme encoded by the ATIC gene.

Ramond et al. (2020) reported 3 additional patients with ATIC deficiency, a 7-year-old boy (patient 1) and 2 sisters, aged 19 and 9 years (patients 2 and 3, respectively). The authors also provided an update of the original 4-year-old patient with ATIC deficiency reported by Marie et al. (2004), who was then 19 years old. All 4 patients had neurodevelopmental impairment, which was severe in patient 1 and profound in the other 3. All 4 had visual impairment and severe scoliosis. Dysmorphic features were reported in all 4 and included an upturned nose, coarse facies, elbow skin dimples, and/or synophrys. All except patient 1 had epilepsy. Patient 1 had liver abnormalities, including hepatomegaly, steatosis, and mild hepatic insufficiency. He experienced frequent vomiting episodes associated with hepatic cytolysis, which appeared to be triggered by hyperthermia or infections. Patient 2 had a severe aortic coarctation, which was also present in a deceased monozygotic twin. All 4 patients had elevated AICA-riboside, SAICA-riboside, and succinyladenosine in the urine. Brain MRI showed signal abnormalities in the dorsal nuclei of the brainstem, a thick corpus callosum, and delayed myelination in patient 3. Brain MRI was normal in patients 1 and 4.

Park et al. (2024) reported a 17-year-old patient, born of consanguineous Syrian parents, with AICA-ribosiduria. He presented at 7 years of age with abnormal movements and epileptiform abnormalities on EEG. At 14 years of age, he developed focal seizures, and a brain MRI showed supratentorial atrophy with cortical thinning. He had impaired intellectual development. An ophthalmologic examination showed pale optic discs and reduced pigment epithelium outside the macula.

Park et al. (2024) treated a 17-year-old patient with AICA-ribosiduria with a purine-rich diet to suppress de novo protein synthesis and favor the purine salvage pathway. Urine excretion of AICA-riboside and succinyladenosine was reduced after initiation of the diet, and the patient experienced slightly improved visual acuity and increased alertness.

Marie et al. (2004) performed sequence analysis of the ATIC gene in their patient with AICA-ribosiduria and found compound heterozygosity for mutations. A missense mutation (K426R; 601731.0001) in the transformylase region was inherited from the father, and a frameshift mutation caused by a duplication/deletion event (601731.0002) was inherited from the mother. The missense mutation was located within a conserved region implicated in the binding of a potassium ion in the avian protein (Greasley et al., 2001). This potassium ion has been proposed to play a key role in stabilization of the tertiary structure of the protein. In expression studies, recombinant protein carrying the K426R mutation completely lacked AICAR-TF activity but still showed IMP-CH activity.

Ramond et al. (2020) identified heterozygosity for the K426R mutation in the ATICD gene by direct gene sequencing in 2 French sisters (patients 2 and 3) with AICA-ribosiduria and elevated AICA-riboside, SAICA-riboside, and succinyladenosine in the urine. A second mutation in the ATIC gene was not identified, but the K426R mutation was found in homozygous state in transcript studies, suggesting the presence of a noncoding variant causing RNA instability on the second allele. Ramond et al. (2020) identified compound heterozygosity for mutations in the ATIC gene (A136T, 601731.0003; K552X, 601731.0004) in a 7-year-old boy with AICA-ribosiduria (patient 1). The A136T mutation is located next to an amino acid that is known to be crucial for the cyclohydrolase activity of dimeric ATIC. Ramond et al. (2020) hypothesized that the A136T mutation could decrease the cyclohydrolase activity of ATIC rather than the transformylase activity, possibly leading to a less severe disease presentation in patient 1 compared to other patients.

In skin fibroblasts derived from the patient reported by Marie et al. (2004), Baresova et al. (2012) found that immunostaining for ATIC was almost undetectable and that there was no signal overlap with other enzymes of the de novo purine synthesis (DNPS) pathway in a purine-depleted medium compared to controls, suggesting impaired assembly of the purinosome. Baresova et al. (2012) suggested that ATIC deficiency and altered purinosome formation could explain the accumulation of AICA-riboside and other cytotoxic intermediates of the DNPS pathway in patient tissues.