{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:49:42Z","timestamp":1784080182641,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003336","name":"Bulgarian National Science Fund","doi-asserted-by":"publisher","award":["KP-06-N33\/5 from 13.12.2019"],"award-info":[{"award-number":["KP-06-N33\/5 from 13.12.2019"]}],"id":[{"id":"10.13039\/501100003336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The genetic bases of Alzheimer\u2019s disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C&gt;T; and rs121908641, p.Gly390Arg, G&gt;A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.<\/jats:p>","DOI":"10.3390\/genes15060753","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T10:43:42Z","timestamp":1717757022000},"page":"753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer\u2019s Disease or Frontotemporal Dementia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6441-629X","authenticated-orcid":false,"given":"Sena","family":"Karachanak-Yankova","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"},{"name":"Department of Genetics, Faculty of Biology, Sofia University \u2018St. Kliment Ohridski\u2019, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitar","family":"Serbezov","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgi","family":"Antov","sequence":"additional","affiliation":[{"name":"Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2389-2702","authenticated-orcid":false,"given":"Mikaela","family":"Stancheva","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Biology, Sofia University \u2018St. Kliment Ohridski\u2019, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savina","family":"Hadjidekova","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2027-6122","authenticated-orcid":false,"given":"Draga","family":"Toncheva","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"},{"name":"Bulgarian Academy of Sciences, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6033-3566","authenticated-orcid":false,"given":"Anastas","family":"Pashov","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diyana","family":"Belejanska","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital \u2018Alexandrovska\u2019, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yavor","family":"Zhelev","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital \u2018Alexandrovska\u2019, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya","family":"Petrova","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital \u2018Alexandrovska\u2019, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shima","family":"Mehrabian","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital \u2018Alexandrovska\u2019, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latchezar","family":"Traykov","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital \u2018Alexandrovska\u2019, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. 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