Homocystinuria due to MTHFR deficiency

MTHFR is an enzyme relevant to amino acid processing and is involved in the conversion of homocysteine to methionine. A drastic decrease in MTHFR function can trigger homocystinuria.

Homocystinuria is an inherited pathology that affects the metabolism of homocysteine, an amino acid essential for cell and tissue growth. This metabolism defect is mainly due to deficiency of the enzyme cystathionine beta synthase or CBS, which is known as classical homocystinuria, but there are other types of homocystinuria such as that caused by a deficiency of MTHFR, MTR, MTRR and MMADHC, and other associated defects such as methylmalonic acidemia type cblC, cblD, and cblD.

Homocystinuria can occur when the body does not produce enough of the MTHFR enzyme or the enzyme produced is not functional. The main function of the MTHFR enzyme is to catalyze the conversion of homocysteine to methionine, two highly relevant amino acids. Thus, when there is a deficiency in MTHFR, there is an increase in homocysteine levels and a decrease in methionine levels in blood and urine, which triggers the development of the characteristic clinical picture of the disease.

Homocystinuria affects at least 1 in 200,000 to 335,000 people worldwide.


MTHFR deficiency homocystinuria is a multisystem disorder affecting the connective tissue, musculature, central nervous system and cardiovascular system. Symptoms may appear in the first year of life (apnea, microcephaly and seizures) or in adulthood, in which cognitive impairment, psychiatric disorders and strokes mainly occur. Generally, the earlier the symptoms appear, the greater the severity. Some adult patients may be asymptomatic.

Elevated plasma homocysteine levels may also be due to other causes such as nutritional deficiencies of vitamin cofactors, certain medications or the presence of other conditions. Other factors associated with increased homocysteine are age, male sex, smoking, coffee consumption, high blood pressure, unfavorable lipid profile, elevated creatinine and poor diet.

Disease management

Treatment with a special diet and drugs can prevent the development of the complications mentioned above, but it must be started in the first years of life to be truly effective. Therefore, it is of paramount importance to study and know the predisposition to develop the disease.

Genes analyzed



Burda P, Suormala T, Heuberger D, et al . Functional characterization of missense mutations in severe methylenetetrahydrofolate reductase deficiency using a human expression system. J Inherit Metab Dis. 2017 Mar;40(2):297-306.

Burda P, Schäfer A, Suormala T, et al . Insights into severe 5,10-methylenetetrahydrofolate reductase reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat. 2015 Jun;36(6):611-21.

Froese DS, Huemer M, Suormala T, et al . Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency. Hum Mutat. 2016 May;37(5):427-38.

Goyette P, Christensen B, Rosenblatt DS, Rozen R . Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996 Dec;59(6):1268-75.

Strauss KA, Morton DH, Puffenberger EG, et al . Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab. 2007 Jun;91(2):165-75.

Wiedemann A, Chery C, Coelho D, et al . Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis. J Hum Genet. 2020 Jan;65(2):91-98.

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