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Key Points

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  • Disease summary:

    • Homocysteine (Hcy) is a sulfur-containing amino acid whose metabolism stands at an intersection of two biochemical pathways. A remethylation pathway converts Hcy to methionine, and requires the presence of folate and vitamin B12, while a trans-sulfuration pathway converts Hcy to cystathionine and cysteine in a reaction requiring vitamin B6.

    • Important monogenic forms of hyperhomocysteinemia (HHcy) include the following:

    • Cystathionine beta-synthase (CBS) deficiency, also known as classic homocystinuria, is associated with a skeletal and ocular phenotype similar to Marfan syndrome, as well as variable developmental delay and a strong predisposition to thromboembolism; around 50% of cases respond to supplementation with vitamin B6.

    • Disorders of B12 metabolism: several disorders of intermediary cobalamin metabolism (CblC, CblD, CblE, CblF, and CblG diseases) as well as transcobalamin deficiency can cause moderate-to-severe HHcy; treatment is centered around daily hydroxocobalamin.

    • Mutations and common polymorphisms of methylenetetrahydrofolate reductase (MTHFR) cause HHcy of variable severity in both the homo- and heterozygous states.

    • Multifactorial HHcy is also associated with a range of common adult diseases including thrombophilia, coronary artery disease, stroke, neuropsychiatric disease, and osteoporosis.

  • Hereditary basis:

    • CBS deficiency, most cobalamin disorders and MTHFR deficiency follow autosomal recessive inheritance. Milder forms of HHcy follow complex or multifactorial patterns of inheritance.

  • Twin studies:

    • In a large Danish twin study, the impact of the MTHFR locus was estimated to explain 53% of the total phenotypic variation in Hcy concentrations in persons 18 to 39 years old, and 24% in persons 40 to 65 years old, that is, almost all additive genetic variance. Hcy concentrations have a high heritability that decreases with age.

  • Genome-wide association studies (GWAS):

    • Significant genome-wide associations have been found between total homocysteine (tHcy) and single-nucleotide polymorphisms (SNPs) located near GPR51 (9q22) and MTHFR (1p36). A GWAS looking at the coronary artery disease phenotype noted an association with MTHFD1L, which is important in methionine-homocysteine metabolism.

  • Pharmacogenomics:

    • Common MTHFR polymorphisms (677C>T and 1298A>C) confer increased sensitivity to fluoropyrimidines (eg, 5-FU) and antifolates (eg, methotrexate).

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Diagnostic Criteria and Clinical Characteristics

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Definitions and Epidemiology

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Severe HHcy is generally restricted to individuals with inherited disorders of Hcy metabolism, is defined as tHcy greater than 100 mmol/L. The most recognized etiology of severe HHcy is CBS deficiency, causing classic homocystinuria. In 1975, the first description of CBS deficiency and its association with thrombophilia leading to early stroke and heart attack in untreated patients led the medical community to suspect milder elevations of Hcy as a contributing factor to atherosclerosis pathogenesis. In the general population, this suspicion has been corroborated through large epidemiologic trials, although Hcy is not currently viewed as an important risk factor.

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Mild HHcy is variably defined as tHcy of 12 to 30 mmol/L, and in some literature as 15 to 30 mmol/L while moderate HHcy is defined as tHcy 30 to 100 mmol/L. Mild-to-moderate HHcy of multifactorial etiology appears ...

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