{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:27:08Z","timestamp":1783445228259,"version":"3.54.6"},"reference-count":8,"publisher":"Walter de Gruyter GmbH","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,24]]},"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n \n 5,10-Methenyltetrahydrofolate synthetase (MTHFS) deficiency is an ultra-rare autosomal recessive inborn error of folate metabolism caused by biallelic pathogenic variants in the\n MTHFS<\/jats:italic>\n gene and associated with a severe neurodevelopmental disorder.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n Patients with molecularly confirmed MTHFS deficiency were identified through a comprehensive search of the PubMed database. A total of 12 patients from 10 unrelated families, including our patient, were analyzed. Demographic data, clinical features, biochemical findings, neuroimaging and electrophysiological results, molecular genetic characteristics, treatment responses, and outcomes were systematically compared.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The disorder showed a pan-ethnic distribution. All patients presented with symptoms during the neonatal and\/or infantile period. Clinical features included severe global developmental delay, microcephaly, hypotonia, growth retardation, mild dysmorphic features, and epilepsy. The male-to-female ratio was 1:1, and parental consanguinity was reported in 30\u202f% of families. Laboratory findings revealed macrocytic anemia, hyperhomocysteinemia, and mildly reduced or low\u2013normal cerebrospinal fluid 5-methyltetrahydrofolate levels. Brain magnetic resonance imaging demonstrated cerebral hypomyelination, thinning of the corpus callosum, cerebellar atrophy, vermian hypoplasia, and T2 hypointensity of the basal ganglia. Homozygous variants were identified in 60\u202f% of patients, and missense variants accounted for 50\u202f% of all detected variants. A total of 12 distinct pathogenic variants were reported, with c.434G>A p.(Arg145Gln) being the most recurrent (4\/20 alleles, 20\u202f%). Despite metabolic treatment, no significant clinical improvement was observed. Two patients (17\u202f%) died at an early age, while the remaining patients exhibited severe neurodevelopmental impairment.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n MTHFS deficiency should be considered in the differential diagnosis of patients presenting with severe developmental delay and microcephaly accompanied by isolated hyperhomocysteinemia.<\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/jpem-2026-0073","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T04:55:47Z","timestamp":1779771347000},"page":"681-689","source":"Crossref","is-referenced-by-count":0,"title":["A comparative analysis of all reported patients with MTHFS-related neurodevelopmental disorder"],"prefix":"10.1515","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1401-5233","authenticated-orcid":false,"given":"Mustafa","family":"K\u0131l\u0131\u00e7","sequence":"first","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7212-6866","authenticated-orcid":false,"given":"Suzan","family":"\u0130cil","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4147-3383","authenticated-orcid":false,"given":"Esra","family":"Sayar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4412-6732","authenticated-orcid":false,"given":"Sevgi","family":"Do\u011fan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0147-3811","authenticated-orcid":false,"given":"Gizem","family":"G\u00f6k\u00e7e-Alta\u015f","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4205-9057","authenticated-orcid":false,"given":"Elif","family":"G\u00fcler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Metabolism Unit, University of Health Science, Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3886-3808","authenticated-orcid":false,"given":"Abdullah","family":"Sezer","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics , Ankara Etlik City Hospital , Ankara , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"2026070716574685926_j_jpem-2026-0073_ref_001","doi-asserted-by":"crossref","unstructured":"Rodan, LH, Qi, W, Ducker, GS, Demirbas, D, Laine, R, Yang, E, et al..Undiagnosed Diseases Network (UDN). 5,10-Methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metabol 2018;125:118\u201326. https:\/\/doi.org\/10.1016\/j.ymgme.2018.06.006.","DOI":"10.1016\/j.ymgme.2018.06.006"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_002","doi-asserted-by":"crossref","unstructured":"Romero, JA, Abdelmoumen, I, Hasbani, D, Khurana, DS, Schneider, MC. A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia. Mol Genet Metab Rep 2019;21:100545. https:\/\/doi.org\/10.1016\/j.ymgmr.2019.100545.","DOI":"10.1016\/j.ymgmr.2019.100545"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_003","doi-asserted-by":"crossref","unstructured":"Sakthivel, D, Lei, Y, Cao, X, Finnell, RH. Homozygous mutation in the MTHFS gene May contribute to the development of cerebral folate deficiency syndrome. Reprod Dev Med 2020;4:72\u20137. https:\/\/doi.org\/10.4103\/2096-2924.288022.","DOI":"10.4103\/2096-2924.288022"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_004","doi-asserted-by":"crossref","unstructured":"Cavusoglu, D, Kose, M, Er, E, Elmas, M, Gencpinar, P, Dundar, NO, et al.. A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities. Brain Dev 2022;44:640\u20134. https:\/\/doi.org\/10.1016\/j.braindev.2022.","DOI":"10.1016\/j.braindev.2022.05.008"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_005","doi-asserted-by":"crossref","unstructured":"Vafaee-Shahi, M, Amirkashani, D, Ashrafi, MR, Tahernia, L, Riahi, A. Methenyltetrahydrofolate synthease deficiency (MTHFS deficiency): Novel mutation and brain MRI findings: a case report and glance to other cases. Clin Neurol Neurosurg 2022;215:107153. https:\/\/doi.org\/10.1016\/j.clineuro.2022.107153.","DOI":"10.1016\/j.clineuro.2022.107153"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_006","doi-asserted-by":"crossref","unstructured":"Xu, X, Zhu, J, Fang, L, Zou, Z, Yuan, J, Peng, M, et al.. Exome sequencing identified novel variants in three Chinese patients with 5,10-methenyltetrahydrofolate synthetase deficiency. Front Genet 2023;14:1236849. https:\/\/doi.org\/10.3389\/fgene.2023.1236849.","DOI":"10.3389\/fgene.2023.1236849"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_007","doi-asserted-by":"crossref","unstructured":"Liepina, L, Smith, DEC, Huidekoper, H, Zeidler, S, Wamelink, M, de Wit, MC, et al.. 5,10-methenyltetrahydrofolate synthetase deficiency: an extreme rare defect of folate metabolism in two Dutch siblings. JIMD Rep 2024;65:49\u201355. https:\/\/doi.org\/10.1002\/jmd2.12409.","DOI":"10.1002\/jmd2.12409"},{"key":"2026070716574685926_j_jpem-2026-0073_ref_008","doi-asserted-by":"crossref","unstructured":"Fowler, B, Froese, DS, Watkins, D. Disorders of cobalamin and folate transport and metabolism. In: Saudubray, JM, Baumgartner, MR, Garc\u00eda-Cazorla, \u00c1, Walter, JH, editors. Inborn Metabolic Diseases Diagnosis and Treatment, 7th ed. Germany: Springer-Verlag GmbH part of Springer Nature; 2022:511\u201331\u00a0pp.","DOI":"10.1007\/978-3-662-63123-2_28"}],"container-title":["Journal of Pediatric Endocrinology and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/jpem-2026-0073\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/jpem-2026-0073\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:07:15Z","timestamp":1783444035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/jpem-2026-0073\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":8,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,2,3]]},"published-print":{"date-parts":[[2026,7,24]]}},"alternative-id":["10.1515\/jpem-2026-0073"],"URL":"https:\/\/doi.org\/10.1515\/jpem-2026-0073","relation":{},"ISSN":["0334-018X","2191-0251"],"issn-type":[{"value":"0334-018X","type":"print"},{"value":"2191-0251","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}