National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Homocystinuria

Homocystinuria refers to a group of inherited disorders in which the body is unable to process certain building blocks of proteins (amino acids) properly. This leads to increased amounts of homocysteine and other amnio acids in the blood and urine. The most common type of genetic homocystinuria, called CBS deficiency, is caused by the lack of an enzyme known as cystathionine beta-synthase (CBS). Most states in the United States test for homocystinuria due to CBS deficiency at birth by newborn screening.   Other types are less common, and are caused by different missing or non-working enzymes.  Homocystinuria can affect the eyes, skeleton, central nervous system and the blood clotting system. Mutations in the MTHFR, MTR, MTRR and MMADHC genes can cause homocystinuria. All these forms of homocystinuria are inherited in an autosomal recessive manner.[1] Treatment and long-term outlook varies depending upon the cause of the disorder.
Last updated: 12/28/2018

Symptoms of the most severe form of homocystinuria will start in infancy or early childhood. he first of these symptoms may be poor growth and failure to gain weight.[1][2][3] Other people with homocystinuria may not have any symptoms until adulthood. The most common symptom seen in adults with homocystinuria is an abnormal blood clot.[3]

Other symptoms of untreated homocystinuria can include:

Eye: 
• Dislocation of the lens of the eye
• Nearsightedness

Skeletal: 
• Caved-in chest (pectus excavatum)
• Curvature of the spine (scoliosis)
• Long, thin bones
• Osteoporosis (weak, brittle bones)

Central nervous system: 
• Learning and intellectual disabilities
• Psychiatric problems

Blood and heart: 
• Cardiovascular disease
• Abnormal blood clots 

Last updated: 12/28/2018
Homocystinuria can be caused by mutations in several different genes. All of these genes are responsible for making enzymes that are involved in the way our body uses and processes amino acids. The most common gene associated with homocystinuria is the CBS gene that causes a lack of the enzyme, cystathionine beta-synthase. Rarer causes of homocystinuria include mutations in the MTHFR, MTR, MTRR and MMADHC genes.[1] It is not clear why high levels of homocysteine cause the symptoms seen in homocystinuria.

There are other, non-genetic causes of high levels of homocysteine.[4] Non-genetic homocystinuria is not a rare condition. Some of the non-genetic causes are listed here.

• Vitamin B6 or vitamin B12 deficiency
• Folate deficiency 
• Low thyroid hormones (hypothyroidism)
• Obesity
• Diabetes
• High cholesterol
• Physical inactivity
• High blood pressure
• Certain medications (such as carbamazepine, atorvastatin, fenofibrate, methotrexate, phenytoin, and nicotinic acid)
• Smoking
• Advanced age

Last updated: 12/28/2018
The genetic forms of homocystinuria are inherited in an autosomal recessive pattern, which means both copies of the gene in every cell have mutations.[1][2] This means that to have the condition, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with homocystinuria inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to have the condition
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

Last updated: 12/28/2018
Most states in the US test for homocystinuria due to CBS deficiency at birth by newborn screening. A baby that has a positive newborn screening test needs to have additional blood testing to look for high levels of homocysteine and methionine in the blood.  Genetic testing can also be helpful for diagnosis.[1][2]
  
A child or an adult with dislocation of the lens of the eye may also get tested for homocystinuria using blood and urine testing. In addition, a child or adult who has a blood clot, especially at an early age, may also get tested for homocystinuria. 

Last updated: 12/28/2018

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
People who have the most severe form of homocystinuria are put on a special protein-restricted diet to reduce the blood levels of homocysteine and methionine. In addition, they may be given supplements including vitamin B6, vitamin B12, folate and betaine. The recommendation is that these people stay on the protein-restricted diet for life. People with milder forms may be treated with supplements depending on the level of homocysteine in their blood.[3][5]
Last updated: 12/28/2018

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Lowering the level of homocysteine in the blood, either with diet or supplements or both, can prevent symptoms. With treatment, people with the most severe form of homocystinuria can have normal growth and development. Some may still have eye problems or blood clots and should be monitored.[2] Blood clots can be serious and cause organ damage.  

Treatment for milder forms of homocystinuria may depend on clinical symptoms and the level of homocysteine in the blood.[3][4]

Last updated: 12/28/2018
Approximately 1 in 200,000 to 1 in 300,000 people in the US has the most common type of homocystinuria (homocystinuria due to CBS deficiency). In other countries, the prevalence is higher. In Quatar, about 1 in 1,800 people has this disorder and in Norway, about 1 in 6,400 people has it.[1]  World-wide, it is thought that about 1 in 150,000 people has homocystinuria due to either a CBS or an MTHFR gene mutation.[5]  It is unclear how many people have homocystinuria due to other gene mutations.
Last updated: 12/28/2018

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Homocystinuria. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Homocystinuria. This website is maintained by the National Library of Medicine.
  • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
  • The Merck Manuals Online Medical Library provides information on this condition for patients and caregivers. 
  • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Homocystinuria. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • My daughter has homocystinuria and wants to get pregnant. Is there any information about homocystinuria and pregnancy? See answer


  1. Homocystinuria. Genetics Home Reference (GHR). March, 2016; https://ghr.nlm.nih.gov/condition=homocystinuria.
  2. Homocystinuria. Screening, Technology and Research in Genetics (STAR-G). Updated 2/18/2016; http://www.newbornscreening.info/Parents/aminoaciddisorders/CBS.html.
  3. Morris AA, Kozich V, Santra S et al. Guidelines for the diagnosis and treatment of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017; 40(1):49-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203861/pdf.
  4. Varga E and Moll S. Homocysteine and MTHFR Mutations. Circulation. 2015; 132:e6-e9. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.114.013311.
  5. Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H. Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options. Biochem Genet. Apr 2018; 56(1-2):7-21. https://www.ncbi.nlm.nih.gov/pubmed/29094226.