MedGen

Hyperhomocysteinemia refers to above-normal concentrations of plasma/serum homocysteine. Plasma/serum homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins (Malinow and Stampfer, 1994). Hyperhomocysteinemia in isolation may be associated with an increased risk of atherosclerosis and recurrent arterial and venous thrombosis usually in the third or fourth decade of life (review by Welch and Loscalzo, 1998). Homocysteinemia is also a feature of several inherited metabolic disorders, including homocystinuria (236200), due to mutation in the CBS gene (613381), and N(5,10)-methylenetetrahydrofolate reductase deficiency (236250), caused by mutation in the MTHFR gene (607093). Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro; see cblE (236270) and cblG (250940). See also the various forms of combined methylmalonic aciduria (MMA) and homocystinuria due to disorders of cobalamin: cblC (277400), cblD (277410), and cblF (277380). [from OMIM]

A disorder that is caused by the deficiency of a vitamin. The deficiency may result from either suboptimal vitamin intake or conditions that prevent the vitamin''s use or absorption in the body. Representative examples include beriberi caused by thiamine deficiency, scurvy caused by vitamin C deficiency, and rickets caused by vitamin D deficiency. [from NCI]

A deficiency in the intake of energy and nutrients. [from HPO]

A syndrome resulting from the inadequate absorption of nutrients in the small intestine. Symptoms include abdominal pain, bloating, and diarrhea. [from NCI]

Abnormally low concentrations of vitamin B in the blood. [from NCI]

An inherited disorder that affects the metabolism of the amino acids. Representative examples include alkaptonuria, homocystinuria, tyrosinemia, and phenylketonuria. [from NCI]

Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in mildly elevated levels of homocysteine, especially in individuals who are also deficient in folate. In these individuals, a daily supplement of low dose folic acid may reduce and often normalize their homocysteine levels, but this has not been demonstrated to improve health outcomes. A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype). The TT genotype is least common in individuals of African descent (6%). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals. Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, and recurrent pregnancy loss. However, more recent analysis has not found an association between elevated homocysteine levels and the risk of venous thrombosis or the risk of coronary heart disease. MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members. Rarely, more severe variants in the MTHFR gene can be a cause of an autosomal recessive inborn error or metabolism where extremely high levels of homocysteine accumulate in the urine and plasma. This can cause developmental delay, eye disorders, thrombosis, and osteoporosis. But more commonly, homocystinuria is caused by variants in a different gene (cystathionine beta-synthase, CBS). [from Medical Genetics Summaries]