What is Homocystinuria?

Homocystinuria (HO‑mo‑SIS‑tun‑YUR‑ee‑uh) is the term used for several rare genetic disorders (diseases passed down through families) that cause levels of homocysteine to build up in blood and urine. This build-up occurs when the body cannot properly process methionine (meh‑THIGH‑uh‑neen) or homocysteine (HO‑mo‑SIS‑teen)—two very important amino acids. Amino acids are the building blocks that the body uses to make proteins.

High levels of homocysteine and abnormal levels of methionine can cause many different symptoms in the body and lead to serious, lifelong health problems.

The homocystinurias are inherited disorders that are caused by certain genes that are abnormal. In order to have homocystinuria, a person must have inherited an affected gene from both parents.

There are 3 types of homocystinuria

Homocystinuria caused by CBS deficiency

Homocystinuria caused by cystathionine beta-synthase (CBS) deficiency is also called classical homocystinuria. CBS is an enzyme. Enzymes are proteins that regulate the body’s tissues and organs. Specifically, CBS helps convert an important amino acid—homocysteine—to another amino acid that the body needs. When the body does not produce enough CBS, levels of homocysteine and methionine (also an important amino acid) in the blood increase. The high levels of homocysteine cause harmful symptoms to develop.

CBS deficiency is divided into 2 subgroups:

  • People who respond to vitamin B6 (pyridoxine)
  • People who do not respond to vitamin B6. These people may have more severe symptoms.

What are the signs and symptoms of homocystinuria caused by CBS deficiency?

Homocystinuria caused by CBS deficiency can affect many parts of the body:

BRAIN

Learning problems and developmental delays, such as being slow to sit up, walk, or talk

EYES

Problems with the lenses in the eyes, such as lens dislocation or cataracts; nearsightedness (often severe); quivering of the iris (the colored part of the eye)

Bones

Tall, thin body with long arms, legs, fingers and toes; curved spine; osteoporosis (brittle or weak bones)

Blood

Development of blood clots

Infants with CBS deficiency appear to be normal at birth but, if not treated, will slowly develop symptoms.

  • Symptoms may appear for the first time at any age.
  • A person may have one or more symptoms.
  • Symptoms can range from mild to severe.
  • Symptoms may vary from person to person.

If you or your loved one has any of these symptoms, talk to your doctor right away.

Early detection and treatment are critical to help reduce serious health problems.

How is homocystinuria caused by CBS deficiency diagnosed?

All states screen newborns for homocystinuria caused by CBS deficiency:

  • The screening tests for high methionine levels.
  • Newborn screening generally identifies infants with CBS deficiency who do not respond to vitamin B6. These infants are likely to have high methionine levels at the time of the test.
  • Newborn screening may miss infants with CBS deficiency who are responsive to vitamin B6. These infants may not have high methionine levels so soon after birth.
  • To learn more about newborn screening, visit babysfirsttest.org.

If someone has a positive newborn screen and/or symptoms that could be signs of homocystinuria caused by CBS deficiency, the doctor will order lab tests. These results may point to a positive diagnosis:

  • High levels of homocysteine in blood and urine
  • High levels of methionine in blood and urine
  • Reduced activity of the CBS enzyme

Once the diagnosis has been made, more tests will be done to measure response to vitamin B6. This will help determine what type of CBS deficiency the person has and will lead to a treatment plan. Genetic testing can confirm the diagnosis.

Medical geneticists are doctors who specialize in diagnosing and treating people with homocystinuria.

How is homocystinuria caused by CBS deficiency treated?

The goal of overall treatment is to prevent or lessen symptoms by reducing the level of homocysteine in the blood. Treatment may include:

  • Taking B vitamins, which may include vitamin B6 (pyridoxine), vitamin B9 (folic acid), and vitamin B12 (colbamin)
  • Eating a diet that is low in natural protein, supplemented with methionine-free amino acid formula and L-cystine
  • Taking CYSTADANE® (betaine anhydrous for oral solution)

Always check with your doctor about what medications and diet are right for you.

Homocystinuria caused by MTHFR deficiency

Homocystinuria caused by 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is very rare. MTHFR is an enzyme. Enzymes are proteins that regulate the body’s tissues and organs. Specifically, MTHFR helps convert an important amino acid—homocysteine—back to methionine, another important amino acid. When the body does not produce enough MTHFR, blood levels of homocysteine increase and blood levels of methionine decrease. This causes harmful symptoms to develop.


What are the signs and symptoms of homocystinuria caused by MTHFR deficiency?

Symptoms of homocystinuria caused by severe MTHFR deficiency can begin in infancy or early childhood. Symptoms are often severe and may include:

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Small head size and
underdeveloped brain at birth

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Developmental delays, such
as being slow to roll over

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Poor muscle tone

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Seizures

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Failure to grow and gain
weight as expected

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Development of
blood clots

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Behaviors that are not
typical for the child’s age

If you or your loved one has any of these symptoms, talk to your doctor right away.

Early detection and treatment are critical to help reduce serious health problems.

How is homocystinuria caused by MTHFR deficiency diagnosed?
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Newborn screening for homocystinuria caused by MTHFR deficiency is not available in any state at this time.

If your child has symptoms that could be signs of homocystinuria caused by MTHFR deficiency, your doctor will order lab tests. These results may point to a positive diagnosis:

  • High levels of homocysteine in blood and urine
  • Low levels of methionine in blood and urine
  • Reduced activity of the MTHFR enzyme

Genetic testing can confirm the diagnosis.

Medical geneticists are doctors who specialize in diagnosing and treating people with homocystinuria.

How is homocystinuria caused by MTHFR deficiency treated?

The goal of overall treatment is to lessen symptoms by reducing the level of homocysteine and maintaining a normal level of methionine in the blood. Treatment may include:

  • Taking CYSTADANE® (betaine anhydrous for oral solution)
  • Taking methionine (an amino acid)
  • Taking the supplement folinic acid/5-Methylfolate

Always check with your doctor about what therapies are right for you.

Homocystinuria caused by cbl defects

Homocystinuria caused by cobalamin cofactor metabolism (cbl) defects occurs when the body cannot properly process cobalamin (vitamin B12). This activity is essential for converting an important amino acid—homocysteine—back to methionine, another important amino acid. When the body cannot process vitamin B12 as it should, blood levels of homocysteine increase, and blood levels of methionine decrease. This causes harmful symptoms to develop.

The body goes through a series of steps to process vitamin B12. Errors can occur in each of these steps. This leads to many types of cbl defects that cause homocystinuria: cblC, cblD, cblE, cblF, cblG, cblJ, and cblX.

By far the most common and best understood type of cbl defects is cblC defect. CblC defect causes two disorders: homocystinuria and methylmalonic acidemia (MMA). MMA causes methylmalonic acid to build up in the blood. The body makes tiny amounts of methylmalonic acid when digesting protein. But a high level of methylmalonic acid in the blood can also cause harmful symptoms to develop. CblD, cblF, cblJ, and cblX defects also cause both homocystinuria and MMA.


What are the signs and symptoms of homocystinuria caused by cblC defect?

Symptoms of homocystinuria caused by cblC defect can develop for the first time at any age and can vary greatly from person to person. Symptoms may include:

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Newborns

Small size overall; small head and underdeveloped brain; poor muscle tone; failure to grow; failure to nurse; vomiting

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Infants

Not wanting to nurse or take a bottle; failure to grow and gain weight as expected; poor muscle tone; wandering eye movements; seizures or other brain disorders; vomiting

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Toddlers and Young Children

Failure to grow and gain weight as expected; poor head growth; anemia; developmental delay, such as slow to walk or talk; seizures or other brain disorders

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Adolescents and Adults

Symptoms related to mental functioning and behavior, such as personality changes, hallucinations (seeing or hearing things that aren’t there), poor memory, and poor performance in school or at work; spinal cord degeneration

Although less is known about other cbl defects that cause homocystinuria, they have many of the same symptoms as cblC defect.

If you or your loved one has any of these symptoms, talk to your doctor right away.

Early detection and treatment are critical to help reduce serious health problems.

How is homocystinuria caused by cbl defects diagnosed?

Newborn screening for homocystinuria caused by cblC or cblD defect is done in most, but not all, states. To learn if this test is offered in your state, visit babysfirsttest.org.

If someone has a positive newborn screen and/or symptoms that could be signs of homocystinuria caused by cbl defects, your doctor will order lab tests. These results may point to a positive diagnosis for most types of cbl defects, including cblC defect:

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  • High levels of homocysteine in blood and urine
  • Low levels of methionine in blood and urine
  • High levels of methylmalonic acid in blood and urine (indicates methylmalonic acidemia, which always occurs with cblC defect and also occurs with some other cbl defects)

Genetic testing can confirm the diagnosis.

Medical geneticists are doctors who specialize in diagnosing and treating people with homocystinuria.

How is homocystinuria caused by cbl defects treated?

The goal of overall treatment is to prevent or lessen symptoms by reducing the levels of homocysteine and maintaining normal levels of methionine in the blood. Treatment may include:

  • Getting B12 (hydroxocobalamin) shots
  • Taking CYSTADANE® (betaine anhydrous for oral solution)
  • Taking methionine (an amino acid)
  • Taking the supplement folate/folinic acid

Always check with your doctor about what therapies are right for you.

Where can I get more information and support?

If you or your child is diagnosed with homocystinuria, you’ll want to find out as much as you can about the disease. The following educational and advocacy groups provide information about rare genetic disorders, including the different types of homocystinuria. You can explore these groups online.

HCU Network America logo

HCU Network America

The mission of the HCU Network America is to help patients with homocystinuria (HCU) and related disorders manage their disease and to find a cure.

Organic Acidemia Association logo

Organic Acidemia Association

The Organic Acidemia Association is a patient advocacy organization that provides support and information for people with inherited metabolic disorders. Homocystinuria caused by several cobalamin defects—cblC, cblD, cblF, cblJ, and cblX—is included as a part of the group’s advocacy for methylmalonic acidemia (MMA).

National Organization for Rare Disorders (NORD) logo

NORD - National Organization for Rare Disorders

NORD is patient advocacy organization dedicated to helping people with rare diseases. NORD provides information on homocystinuria due to CBS deficiency.

INDICATIONS AND USAGE

CYSTADANE (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease high homocysteine blood levels. Homocystinuria is a rare genetic disorder in which there is an abnormal accumulation of the amino acid homocysteine in the blood and urine. The following are considered to be homocystinuria disorders:

  • Cystathionine beta-synthase (CBS) deficiency
  • 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
  • Cobalamin cofactor metabolism (cbl) defects

IMPORTANT SAFETY INFORMATION

  • Hypermethioninemia: CYSTADANE may worsen high methionine blood levels in patients with CBS deficiency. Accumulation of excess fluid in the brain has been reported.
  • Monitoring: If you have been told you have CBS deficiency, your doctor will be monitoring your methionine blood levels to see if changes in your diet and dosage are necessary.
  • Most common side effects were nausea and gastrointestinal distress, based on a survey of doctors.
  • To report SUSPECTED SIDE EFFECTS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1‑800-FDA-1088 or www.fda.gov/medwatch.
  • Pregnancy: The effects of CYSTADANE on pregnancy and an unborn baby are not known.
  • Nursing women: Breast-feeding by a patient taking CYSTADANE is not recommended.
  • Pediatrics: Patients ranging in age from 24 days to 17 years have been treated with CYSTADANE. Children younger than 3 years of age may benefit from slowly adjusting the dose until the desired medical result is achieved.
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IMPORTANT SAFETY INFORMATION

  • Hypermethioninemia: CYSTADANE may worsen high methionine blood levels in patients with CBS deficiency. Accumulation of excess fluid in the brain has been reported.
  • Monitoring: If you have been told you have CBS deficiency, your doctor will be monitoring your methionine blood levels to see if changes in your diet and dosage are necessary.