PAICS deficiency is another newly described disorder connected with de novo purine synthesis (DNPS). There are currently two publications describing this disease [1, 2]. Two patients from Faroe Island had severe malformations and due to hypotention and hypoxia they died few days after birth [1]. Another two patients were diagnosed recently. They were born at term after uncomplicated pregnancy. Later in life they exhibited progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation and retinopathy [2]. Unfortunatelly, no treatment is possible at this time.
PAICS deficiency is caused by mutations in PAICS gene: c.158A>G (p.K53R), c.535 T > C (p.S179P) and c.1207 C > T (p.R403*). PAICS gene codes bifunctional enzyme PAICS. PAICS has two catalytic domains. First, AIR carboxylase (AIRc, EC 4.1.1.21) and second, SAICAR synthetase (SAICARs, EC 6.3.2.6) that produces SAICAR (the substrate for ADSL enzyme). Mutations in PAICS gene lead to reduction of enzymatic activity and as consequence accumulation of its substrates occurs in the cells and potentially in the body fluids of the patients. Mutations can also destabilize octameric assembly and lead to aberrant communication between AIRc and SAICARs domains.
Diagnosis of this rare disorder can be done throught genetic testing and/or look at metabolic profile of purines in body fluids (plasma, urine).
Figure 1: Role of PAICS enzyme in de novo purine synthesis (DNPS). Mulfunction of PAICS leads to disruption of DNPS and accumulation of two substrates of PAICS enzyme - specifically AIR (aminoimidazole ribotide) and/or CAIR (carboxyamminoimidazole ribotide).
[1] Pelet A, Skopova V, Steuerwald U, Baresova V, Zarhrate M, Plaza JM, Hnizda A, Krijt M, Souckova O, Wibrand F, Andorsdóttir G, Joensen F, Sedlak D, Bleyer AJ, Kmoch S, Lyonnet S, Zikanova M. PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. Hum Mol Genet. 2019 Nov 15;28(22):3805-3814. doi: 10.1093/hmg/ddz237. PMID: 31600779.
[2] Weng WC, Skopova V, Baresova V, Liu YL, Hsueh HW, Chien YH, Hwu WL, Souckova O, Hnizda A, Kmoch S, Lee NC, Zikanova M. Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases. Eur J Hum Genet. 2024 Nov 27. doi: 10.1038/s41431-024-01752-2. Epub ahead of print. PMID: 39604553.