{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T01:02:36Z","timestamp":1794445356959,"version":"4.9.1"},"reference-count":46,"publisher":"BMJ","issue":"11","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Clin Pathol"],"accepted":{"date-parts":[[2022,9,2]]},"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>Homocystinuria (HCU) refers to a group of inherited disorders of homocysteine metabolism associated with high blood homocysteine concentration, thromboembolic tendency and neurocognitive symptoms. The most common causes of a high blood homocysteine relate to underlying vitamin B<jats:sub>12<\/jats:sub> or folate deficiency which must be excluded first. Thereafter, an inherited metabolic condition can be considered.<\/jats:p>\n               <jats:p>The most prevalent inherited disorder of homocysteine metabolism is classical HCU caused by deficiency of the pyridoxine-dependent enzyme, cystathione beta-synthase, which converts homocysteine to cystathionine in the transsulphuration pathway. An alternative route for homocysteine metabolism is its remethylation to methionine by the cobalamin-dependent enzyme, methionine synthase, using the folate derivative, methyltetrahydrofolate, as a methyl donor. Remethylation defects are caused by impaired activity of methionine synthase itself, of an enzyme required to generate its methylcobalamin cofactor from dietary vitamin B<jats:sub>12<\/jats:sub>, or of the enzyme methyltetrahydrofolate reductase (MTHFR), which generates the methyl donor.<\/jats:p>\n               <jats:p>The correct diagnosis can be inferred from additional laboratory investigations including a complete blood count and quantitation of methionine and methylmalonic acid. Methionine is high\/normal in HCU and low in the remethylation disorders. In the latter, cobalamin defects are readily distinguished from MTHFR by a coexisting macrocytic anaemia and further delineated by presence or absence of methylmalonic acid in urine or plasma.<\/jats:p>\n               <jats:p>Lowering homocysteine reverses thromboembolic risk. In HCU, this may be achieved with pyridoxine alone or with betaine as an alternative methyl donor. Some patients additionally follow a methionine-restricted diet. Betaine is the primary treatment for MTHFR and cobalamin disorders are managed with high-dose hydroxocobalamin.<\/jats:p>","DOI":"10.1136\/jcp-2021-208029","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T13:20:16Z","timestamp":1663593616000},"page":"744-750","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Homocystinuria diagnosis and management: it is not all classical"],"prefix":"10.1136","volume":"75","author":[{"given":"Adam","family":"Gerrard","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Birmingham Women\u2019s and Children\u2019s Hospitals NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9621-6468","authenticated-orcid":false,"given":"Charlotte","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, 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