APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: MTHFR

MTHFR deficiency
Methylenetetrahydro- folate reductase deficiency

Mental retardation
Ectopia lentis
Lens dislocation
Cerebral thrombosis

Homocystinuria (MTHFR)

Clinical Characteristics

General description (for patients):

Homocystinuria is a relatively common but treatable genetic condition with severe health implications from early death to disabling strokes and mental retardation.  Early diagnosis and treatment are essential. Individuals often have a light complexion, appear tall, and have long fingers and toes.  Bones may be brittle.  The lenses in the eye are often displaced, and more commonly after about 10 years of age.  Blood clots are a serious risk, causing heart attacks and strokes, and the risk is increased by general anesthesia.

Medical description:  

This is a treatable metabolic disorder with a wide range of clinical manifestations.  Neonates may be hypotonic, suffer from respiratory difficulties, and fail to thrive.  Others live to adulthood with  few symptoms.  Untreated, 66 per cent of patients will have mental retardation, 80 percent have dislocated lenses by age 10.  Clinically detectable thromboembolic events occur in 12- 27 percent of patients.  Major psychiatric disorders occur in about 50 percent.   Major surgery under general anesthesia is complicated by thromboembolic events in 4 percent but the risk can be reduced by meticulous regulation of hydration.   Co-occurrence of factor V Leiden mutations increases the risk of vascular thromboses.  Both methionine and homocystine are elevated in the urine.  Homocystinuria is a disease of multiple etiologies (see Genetics section below).


Homocystinuria is an autosomal recessive disorder most often caused by a deficiency of cystathionine beta-synthase. However, it is a complicated condition with multiple etiologies and subtypes for which a large number of mutations and metabolic errors have been reported.  Other causes of the same syndrome may be defects in absorption and metabolism of B12, methylcobalamin and transcobalamin II deficiencies, among others.  The mutations most commonly causing homocystinuria are in the CBS gene located on chromosome 21 (21q22.3).  However, another common inborn error causing folate metabolism deficiencies, methylenetetrahydrofolate reductase deficiency, can cause another form of homocystinuria with severe mental deficits and early death if untreated.   This variant, caused by homozygous mutations in the MTHFR gene on chromosome 1 (1p36.3) has been identified (c.1129C>T) in the Amish of Pennsylvania.


Neonatal methionine restriction helps prevent mental retardation, and reduces the risk of lens dislocation and seizures.  Patients with the folate metabolism deficiencies can benefit from the administration of folate and pyridoxine if administered early.  Amish patients with this type have benefitted from early treatment with betaine.


Largely dependent on type and treatment.  Homocystinuria in all its variations can cause serious and widespread health problems, from early death to disabling complications.  Prompt diagnosis and treatment are essential.

Ancillary treatments and support:

In the absence of complications and with closely monitored care, most can live productive lives.  Of primary importance is careful monitoring by physicians as recommended.

Specialists and specialty centers:

Nutritionist, pediatrician, neurologist, neonatologist, cardiologist, physical therapist.


Goyette, P., Christensen, B., Rosenblatt, D.S., and 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. 59: 1268-1275, 1996. PubMed ID: 8940272

Strauss, K.A., Morton, D.H., Puffenberger, E.G., Hendrickson, C., Robinson, D.L., Wagner, C., Stabler, S.P., Allen, R.H., Chwatko, G., Jakubowski, H., Niculescu, M.D., and Mudd, S.H.:  Prevention of brain disease from severe 5,10-methyenetetrahydrofolate reductase deficiency.  Molec. Genet. Metab. 91: 165-175, 2007.  PubMed ID: 17409006

Rozen, R.:  Molecular genetics of methylenetetrahydrofoloate reductase deficiency.  J. Inherit. Metab. Dis. 19: 589-594, 1996. PubMed ID: 8892013

Wendel, U., Bremer, H.J.:  Betaine in the treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency.  Europ. J. Pediat. 142: 147-150, 1984.  PubMed ID: 6381059


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