TY - CHAP M1 - Book, Section TI - Hyperhomocysteinemia A1 - Weisfeld-Adams, James A1 - Kirmse, Brian A2 - Murray, Michael F. A2 - Babyatsky, Mark W. A2 - Giovanni, Monica A. A2 - Alkuraya, Fowzan S. A2 - Stewart, Douglas R. PY - 2014 T2 - Clinical Genomics: Practical Applications in Adult Patient Care AB - 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). SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/29 UR - accessbiomedicalscience.mhmedical.com/content.aspx?aid=1102703192 ER -