Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form-called cystathionine beta-synthase deficiency, is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.

Less common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and a blood disorder called megaloblastic anemia. Mutations in the CBSMTHFRMTR, and MTRR genes cause homocystinuria, and it is inherited in an autosomal recessive manner. Treatment varies depending upon the cause of the disorder.


The signs and symptoms of homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood. Symptoms of homocystinuria can be:

  • dislocation of the lens in the eye
  • skeletal abnormalities
  • intellectual disability
  • seizures

Newborn infants appear healthy. Early symptoms, if present at all, are not obvious.


In homocysteinuria, the generation and degredation of amino acids is disturbed. This leads to an accumulation of homocysteine in the body, which is toxic in higher concentrations. The toxic effects of homocysteine lead to mental retardation, eye problems, skeletal and vascular abnormalities.

Mutations in the CBS, MTHFR, MTR, MTRR, and MMADHC genes cause homocystinuria and it is inherited in an autosomal recessive manner.

For a child to be seriously affected by Homocystinuria, it must inherit the non-working genes from both parents (autosomal recessive trait). Mutations in the CBS gene cause the most common form of homocystinuria. The CBS gene provides instructions for producing an enzyme called cystathionine beta-synthase. This enzyme acts in a chemical pathway and is responsible for converting the amino acid homocysteine to a molecule called cystathionine. As a result of this pathway, other amino acids, including methionine, are produced. Mutations in the CBS gene disrupt the function of cystathionine beta-synthase, preventing homocysteine from being used properly. As a result, this amino acid and toxic byproducts substances build up in the blood. Some of the excess homocysteine is excreted in urine.

Rarely, homocystinuria can be caused by mutations in several other genes. The enzymes made by the MTHFR, MTR, MTRR, and MMADHC genes play roles in converting homocysteine to methionine. Mutations in any of these genes prevent the enzymes from functioning properly, which leads to a buildup of homocysteine in the body. Researchers have not determined how excess homocysteine and related compounds lead to the signs and symptoms of homocystinuria.

The harmful effects of an accumulation of homocysteine is due to

  • Production of oxidants (reactive oxygen species) generated during oxidation of homocysteine to homocystine, and disulphides in the blood. These could oxidize membrane lipids and proteins
  • Thiolation, i.e. reaction with protein thiol groups leading to the formation of disulphides
  • Its conversion to highly reactive thiolactone which could react with the proteins forming -NH-CO- adducts, thus affecting the body proteins and enzymes.


Genetic counseling is recommended for prospective parents with a family history of homocystinuria. Intrauterine diagnosis of homocystinuria is available. This involves culturing amniotic cells or chorionic villi to test for cystathionine synthase (the enzyme that is missing in homocystinuria). If there are known specific genetic mutations in the parents or family, samples from chorionic liquid or amniocentesis can be used to test for these mutations.

If discovered early, these symptoms can be avoided or worsen and treated by the lifelong addition of vitamins B6 and B12, combined with a food diet with low methionine levels.


The diagnosis of homocystinuria is suspected in individuals with findings that range from multiple organ disease beginning in infancy or early childhood to only thromboembolism expressed in early to middle adult years.

Newborn screening diagnosis:

Homocystinuria can be detected by screening the blood of a newborn for an excess of methionine (hypermethioninemia). This can be done through a Guthrie blood spot card by either a bacterial assay or tandem mass spectrometry. If the initial screening test result exceeds the cut-off level of methionine, follow-up testing is required.

If the second test confirms hypermethioninemia, quantitative plasma and urine amino acid testing with attention to concentrations of methionine, homocystine, and total homocysteine is performed to confirm or exclude the diagnosis of homocystinuria.

It is important to note that the screening is for methionine and not for homocystine or homocysteine. Thus, other causes of elevated total homocysteine, such as disorders of remethylation (e.g., methylenetetrahydrofolate reductase deficiency and the cobalamin defects) are not detected, because the methionine level in these disorders is reduced (or normal).

Virtually, all infants with homocystinuria detected by newborn screening programs have had pyridoxine non-responsive homocystinuria. It is likely that infants who are pyridoxine responsive do not have increased methionine during the first two to three days of life, when the newborn screening specimen is obtained.

While performing a physical examination on the child, the health care provider may notice a tall, thin (Marfanoid) stature combined with the symptoms mentioned above.

Further tests are:

  • Amino acid screen of urine
  • Genetic testing
  • Liver biopsy and enzyme assay
  • Skeletal x-ray
  • Skin biopsy with a fibroblast culture
  • Standard eye (ophthalmic) exam


Vitamin B6 therapy can help about half of people affected by the condition. If the diagnosis is made while a patient is young, starting a low methionine diet quickly can prevent some mental retardation and other complications of the disease. For this reason, some states screen for homocystinuria in all newborns. Patients with persistent rises in blood homocysteine levels are at increased risk for blood clots. Clots can cause significant medical problems and shorten lifespan.

Possible Complications:

Most serious complications result from blood clots. These episodes can be life threatening. Dislocated lenses of the eyes can severely impair vision. Lens replacement surgery should be considered. Mental retardation is a serious consequence of the disease. However, it can be lessened if diagnosed early.


Treatment varies depending upon the cause of the disorder. The principles of treatment are to control the elevated homocystine concentrations in the body as well as to prevent further complications like thrombosis. This can be done by the intake of vitamins in about half of the cases, as well as choosing a diet with specific protein content.

Half of the patients respond to high doses of vitamin B6 (approximately 200-1000 mg/day), which then needs to be taken livelong.

Those who do not respond to this require a low methionine diet by restricting natural protein intake. However, to prevent protein malnutrition, a methionine-free amino acid formula supplying the other amino acids (as well as cysteine which may be an essential amino acid in homocysteinuria) is provided. The amount of methionine required is calculated by a metabolic dietician and supplied in natural food and special low-protein foods and monitored on the basis of plasma concentrations of homocystine and total homocysteine as well as methionine.

Most patients will need treatment with Betaine (Cystadane) at 6-9 g/day in two divided doses. Betaine provides an alternate remethylation pathway to convert excess homocysteine to methionine, which in turn lowers the homocysteine concentrations. This may help to prevent complications, particularly thrombosis

Folate and vitamin B12 optimize the conversion of homocysteine to methionine by methionine synthase, which helps to decrease the plasma homocystine concentration. When the red blood cell folate concentration and serum B12 concentration are reduced, folic acid is given orally at 5 mg per day and vitamin B12 is given as hydroxocobalamin at 1 mg per month.

Neither a low-methionine diet nor medication will improve existing mental retardation. Medication and diet should be closely supervised by a physician with experience treating homocystinuria


Refer to research Publications.