Homocystinuria diagnosis and management: it is not all classical

Abstract

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.

Profiling of Homocysteine Metabolic Pathway Related Metabolites in Plasma of Diabetic Mellitus Based on LC-QTOF-MS

“…In addition, studies have shown that certain diseases such as neonatal defects, arteriovenous thrombosis, diabetes, stroke, Alzheimer’s, and Parkinson’s disease are also associated with abnormal Hcy metabolism [ 9 , 11 , 12 ]. Since the high concentrations of Hcy can induce the risk of various diseases, a variety of methods for the detection of Hcy have been developed clinically to facilitate clinical diagnosis and prevention [ 13 , 14 , 15 ]. The biomarkers of DM have been studied by metabolomics, which also involve the metabolites on Hcy metabolism [ 16 ].…”

Homocystinuria: a commentary

“…In the accompanying best practice, the authors discuss the diagnosis and management of homocystinuria, with particular emphasis on inherited metabolic disorders affecting the cobalamin pathway 16. In table 1 of the best practice paper, the authors outline the causes of mild hyperhomocystinaemia (HHC) (15–40 µmol/L), moderate (41–100 µmol/L) and severe (>100 µmol/L) 10 16.…”

“…In the accompanying best practice, the authors discuss the diagnosis and management of homocystinuria, with particular emphasis on inherited metabolic disorders affecting the cobalamin pathway 16. In table 1 of the best practice paper, the authors outline the causes of mild hyperhomocystinaemia (HHC) (15–40 µmol/L), moderate (41–100 µmol/L) and severe (>100 µmol/L) 10 16. The providence for these cut-offs is mainly derived for cohort, case–controls studies of various sizes and so the CIs on these will be broad, with some overlap, particularly where more than one factor is at play 17.…”

“…Mild to moderately elevated HHC is most commonly due to vitamin B 12 or folate deficiency, less likely to be due to severe B 6 deficiency or hypothyroidism or chronic kidney disease 16 17. While HCY is elevated in both B 12 and folate deficiency, methylmalonic acid (MMA) is elevated only in B 12 and not folate deficiency.…”

“…Following careful evaluation of the biochemistry, NGS (next generation sequencing) panel testing is now first line in confirming the relevant mutation in remethylation disorders but historically such genetic testing was not available and fibroblast testing was the next step. Such enzymatic testing is still used but in the context of lack of access to genetics, or where the yield from genetics is uncertain as in variant of uncertain significance or no identifiable mutation identified with a strong clinical phenotype 16. Another complicating matter is the discovery that epigenetic variants, such as epi-CblC presenting with loss of function affecting cobalamin metabolism, require specific genetic techniques not covered by routine NGS 29…”