From the Guidelines
Elevated homocysteine levels, rather than deficiency, are associated with several genetic disorders, and treatment should focus on lowering homocysteine levels to prevent complications. The most notable genetic disorder associated with elevated homocysteine levels is homocystinuria, caused primarily by mutations in the CBS gene that encodes cystathionine beta-synthase 1. This condition leads to dangerously high homocysteine levels in blood and urine, resulting in complications including thromboembolism, skeletal abnormalities, lens dislocation, and intellectual disability.
Treatment Options
- Treatment typically involves vitamin B6 (pyridoxine) supplementation at doses of 50-500 mg daily, as many patients are B6-responsive 1.
- For non-responsive patients, treatment includes betaine (6-9 g daily divided into 2-3 doses), vitamin B12 (1 mg daily), folate (5 mg daily), and a methionine-restricted diet 1.
- Other genetic conditions causing hyperhomocysteinemia include MTHFR deficiency, methionine synthase deficiency, and cobalamin metabolism disorders, which disrupt the methionine cycle and prevent proper homocysteine metabolism 1.
Importance of Early Diagnosis and Treatment
Early diagnosis through newborn screening and prompt treatment are essential to prevent complications, as homocysteine damages blood vessels and connective tissue through oxidative stress and disruption of normal protein function 1.
Key Considerations
- Elevated homocysteine levels are associated with a 2- to 3-fold increased risk for atherosclerotic vascular disease, including stroke and peripheral arterial disease 1.
- The European Concerted Action Project has estimated that fasting homocysteine concentrations greater than the 80th percentile are associated with a 2-fold increased risk of atherosclerotic vascular disease, independent of traditional risk factors 1.
From the Research
Homocysteine Deficiency/Increase Genetic Diseases
- Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs 2.
- Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven 2.
- Individuals with the MTHFR 677TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD 2.
Genetic Predisposition to Homocysteine-Related Diseases
- The MTHFR gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase 2.
- Homocystinuria is a disorder of sulfur metabolism pathway caused by deficiency of cystathionine β-synthase (CBS) 3.
- Increased homocysteine results in various vascular and neurological complications 3.
Disease Associations with Homocysteine
- More than 100 diseases or conditions are associated with raised concentrations of plasma total homocysteine, including cardiovascular diseases and diseases of the central nervous system 4.
- Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly 4.
- Total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention 4.
Treatment and Prevention
- Folic acid supplementation should be recommended to any patient who has an elevated Hcy level, and this level should be measured and treated at an early age 5.
- Daily supplementation with 0.5-5.0 mg of folic acid typically lowers plasma Hcy levels by approximately 25% 5.
- Vitamin B6 intake, dietary methionine restriction, betaine supplementation, folate and vitamin B12 administration are present strategies to lower cellular and plasma homocysteine levels 3.