Homocystinuria diagnosis and management: it is not all classical

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.