{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:25:13Z","timestamp":1787696713385,"version":"build-2784847793"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Hyperhomocysteinemia in adolescence typically prompts investigation for classical inborn errors of sulfur amino acid metabolism, including cystathionine \u03b2-synthase deficiency and cobalamin-dependent remethylation disorders. However, persistent elevations may also arise from interactions between common genetic polymorphisms and acquired nutritional conditions that alter one-carbon metabolism.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      We report an 18-year-old male with type 1 diabetes mellitus, celiac disease on a strict gluten-free diet, congenital unilateral sensorineural hearing loss, and persistent isolated hyperhomocysteinemia. At age 16, he presented with an acute visual field disturbance and right occipital cortical MRI changes suggestive of ischemia. Plasma homocysteine was persistently between 50 and 65\u00a0\u03bcmol\/L.Extensive metabolic and genetic investigations, including targeted gene panels, whole-exome and research whole-genome sequencing, mitochondrial DNA sequencing, mitochondrial complex activities in fibroblasts, and fibroblast complementation, excluded classical homocystinuria and remethylation defects. Sequential trials of pyridoxine, hydroxocobalamin, and high-dose betaine produced modest or transient improvement. Re-analysis of exome data showed homozygosity for the common\n                      <jats:italic>MTHFR<\/jats:italic>\n                      c.665C&amp;gt;T (p.Ala222Val) variant. Family testing revealed that his father (TT) and mother (CT) had normal homocysteine (10.9 and 10.4\u00a0\u03bcmol\/L), indicating that\n                      <jats:italic>MTHFR<\/jats:italic>\n                      TT alone is insufficient to cause a biochemical phenotype and functions as a susceptibility factor. Combined oral methylfolate (1,000\u00a0\u00b5g daily) and vitamin B12 (cyanocobalamin 1,000\u00a0\u00b5g daily) reduced homocysteine from 66 to 24.6\u00a0\u03bcmol\/L in 8\u00a0weeks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This case illustrates multifactorial hyperhomocysteinemia arising from interactions between celiac disease-related micronutrient vulnerability and reduced\n                      <jats:italic>MTHFR<\/jats:italic>\n                      activity. Recognition of gene-nutrient interactions is important when classical metabolic disorders are excluded and may guide targeted therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1912912","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:10:29Z","timestamp":1787695829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Persistent isolated hyperhomocysteinemia in an adolescent with celiac disease and homozygous MTHFR c.665C&gt;T polymorphism: a multifactorial disturbance of one-carbon metabolism"],"prefix":"10.3389","volume":"17","author":[{"given":"Zainab","family":"Al Masseri","sequence":"first","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian R.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Division of Genome Diagnostics, The Hospital for Sick Children","place":["Toronto, ON, Canada"]},{"name":"Laboratory Medicine and Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Martin","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Guilder","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Inbar-Feigenberg","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.5316","article-title":"Association of homocysteine, methionine, and MTHFR 677C>T polymorphism with rate of cardiovascular multimorbidity development in older adults in Sweden","volume":"3","author":"Calder\u00f3n-Larra\u00f1aga","year":"2020","journal-title":"JAMA Netw. 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