PFAS (Phosphoribosylformylglycinamidine Synthase) is one of the main enzymes involved in de novo purine synthesis. Unlike the others, it catalyzes only one reaction - it converts FGAR (formylglycineamide ribotide) into (FGAMR) formylglycineamidine ribotide [1]. The collaboration with Medical Center in Nederlands led us to discovery of novel disorder called PFAS deficiency and in 2025 we published joined paper describing this new disease [2]. There were examined two patients (one from the Czech Republic and one from the Netherlands). Both of them show mild nerurological impairment, recurrent seizures and are presented with prematurity and short stature. Elevated concentrations of dephosphorylated FGAr was found in urine, lower amount of PFAS enzyme and its lowered activity was found in one of the patients that carries mutations p. Arg811Trp and p.Glu228_Ser230. The patient from Netherland carries homozygous mutation p.Asn264Lys and she declined to go through further examination. Therefore, recombinant protein was prepared and studied. The experiments revealed decreased activity of corresponding mutated protein. The reason, why this disorder is identified now, is due to better instruments that can detect purine intermediates and thanks to the genetic testing as well. The PFAS disorder is probably related to the embryonic lethality of certain PFAS variants and poor clinical recognition of phenotypically mild cases.
[1] Krijt M, Souckova O, Baresova V, Skopova V, Zikanova M. Metabolic Tools for Identification of New Mutations of Enzymes Engaged in Purine Synthesis Leading to Neurological Impairment. Folia Biol (Praha). 2019;65(3):152-157. doi: 10.14712/fb2019065030152. PMID: 31638562.
[2] Zikanova M, Skopova V, Stuurman KE, Baresova V, Souckova O, Hnizda A, Krijt M, Bleyer AJ, Zeman J, Kmoch S. Phosphoribosylformylglycinamidine Synthase (PFAS) Deficiency: Clinical, Genetic and Metabolic Characterisation of a Novel Defect in Purine de Novo Synthesis. J Inherit Metab Dis. 2025 May;48(3):e70041. doi: 10.1002/jimd.70041. PMID: 40421664; PMCID: PMC12107509.