{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:22:00Z","timestamp":1793740920992,"version":"4.6.1"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["NU23\u201001\u201000500"],"award-info":[{"award-number":["NU23\u201001\u201000500"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["CZ.02.01.01\/00\/23_020\/0008540"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_020\/0008540"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["NCLG\u2010LM2023067"],"award-info":[{"award-number":["NCLG\u2010LM2023067"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Univerzita Karlova v Praze","doi-asserted-by":"publisher","award":["UNCE 24\/MED\/022"],"award-info":[{"award-number":["UNCE 24\/MED\/022"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Purine de novo purine synthesis involves 10 reactions catalysed by six enzymes, including phosphoribosylformyglycinamidine synthase (PFAS). To date, genetic defects of three of these enzymes, namely ATIC, ADSL and PAICS, have been characterised in humans. Here, we report for the first time two individuals with PFAS deficiency. Probands were identified through metabolic and genetic screening of neurologically impaired individuals. The pathogenicity of the variants was established by structural and functional studies. Probands C1 and C2 presented with prematurity, short stature, recurrent seizures and mild neurological impairment. C1 had elevated urinary levels of formylglycineamide riboside (FGAr) and bi\u2010allelic PFAS variants encoding the NP_036525.1:p.Arg811Trp substitution and the NP_036525.1:p.Glu228_Ser230 in\u2010frame deletion. C2 is a 20\u2010year\u2010old female with a homozygous NP_036525.1:p.Asn264Lys substitution. These amino acid changes are predicted to affect the structural stability of PFAS. Accordingly, C1 skin fibroblasts showed decreased PFAS content and activity, with impaired purinosome formation that was restored by transfection with pTagBFP_PFAS_wt. The enzymatic activities of the corresponding recombinant mutant PFAS proteins were also reduced, and none of them, after transfection, corrected the elevated FGAR\/r levels in PFAS\u2010deficient HeLa cells. While genetic defects in purine de novo synthesis are typically considered in patients with severe neurological impairment, these disorders, especially PFAS deficiency, should also be considered in milder phenotypes.<\/jats:p>","DOI":"10.1002\/jimd.70041","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T06:12:37Z","timestamp":1748326357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phosphoribosylformylglycinamidine Synthase (\n                    <scp>PFAS<\/scp>\n                    ) Deficiency: Clinical, Genetic and Metabolic Characterisation of a Novel Defect in Purine\n                    <i>de Novo<\/i>\n                    Synthesis"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9375-800X","authenticated-orcid":false,"given":"Marie","family":"Zikanova","sequence":"first","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaclava","family":"Skopova","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra E.","family":"Stuurman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Baresova","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Souckova","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"},{"name":"OMICS Mass Spectrometry Core Facility, Biology Departments, Faculty of Science Charles University, BIOCEV  Vestec Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ales","family":"Hnizda","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matyas","family":"Krijt","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Bleyer","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"},{"name":"Section on Nephrology Wake Forest School of Medicine  Winston\u2010Salem USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Zeman","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislav","family":"Kmoch","sequence":"additional","affiliation":[{"name":"Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University in Prague and General University Hospital in Prague  Czechia Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1152241"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr591"},{"issue":"8411","key":"e_1_2_9_4_1","first-page":"1058","article-title":"An Infantile Autistic Syndrome Characterised by the Presence of Succinylpurines in Body 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