Homocystinuria, MTHFR Deficiency

Clinical Characteristics

Ocular Features

The ocular signs in MTHFR deficiency are likely similar to those found in beta-synthase deficiency (236200) but no comparative study has been reported.  Ectopia lentis is common and the high mobility of the lens carries a significant risk of pupillary block glaucoma and migration into the anterior chamber.

Systemic Features

There is a wide range in clinical disease in MTHFR deficiency but the neurological signs and the progressive of disease seem to be more aggressive than in beta-synthase deficiency (236200) . Neonates may have seizures and failure to thrive but other affected patients may live to adulthood without symptoms.  Early death from neurological complications is more common and the mental retardation is apparently more severe.  There is a serious risk for thromboembolic events which may be life-threatening.  Hyperhomocyteinemia and low plasma methionine are present as is increased homocystine in urine.


Mutations in MTHFR (1p36.3) are responsible for this form of homocystinuria.  Another form, beta-synthase deficiency (236200), is caused by a mutation in the CBS gene.  This is an autosomal recessive disorder.

Treatment Options

Administration of betaine has been reported to reduce the neurological disease but it must be started early before brain damage occurs.  It does not correct hyperhomocysteinemia nor does it correct CNS MTHFR deficiency.  It has also been reported that betaine in combination with folic acid and cobalamin can prevent symptoms.


Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, Stabler SP, Allen RH, Chwatko G, Jakubowski H, Niculescu MD, Mudd SH. Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab. 2007 Jun;91(2):165-75.

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Harrison DA, Mullaney PB, Mesfer SA, Awad AH, Dhindsa H. Management of ophthalmic complications of homocystinuria. Ophthalmology. 1998 Oct;105(10):1886-90.

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Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis. 1996;19(5):589-94. Review.

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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.

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