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Homocystinuria diagnosis and management: it is not all classical
  1. Adam Gerrard1,
  2. Charlotte Dawson2
  1. 1Department of Clinical Chemistry, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK
  2. 2Department of Endocrinology and Metabolism, Queen Elizabeth Hospital Birmingham, Birmingham, UK
  1. Correspondence to Dr Charlotte Dawson, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, UK; Charlotte.Dawson{at}


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 B12 or folate deficiency which must be excluded first. Thereafter, an inherited metabolic condition can be considered.

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 B12, or of the enzyme methyltetrahydrofolate reductase (MTHFR), which generates the methyl donor.

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.

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.

  • Folic Acid
  • Genetic Diseases, Inborn
  • Vitamin B 12

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  • Handling editor Patrick J Twomey.

  • Contributors Both authors have contributed equally to the writing of this article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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