What Genetic Disorders Cause Homocystinuria?

There are three rare, genetic disorders that cause homocystinuria (HO‑mo‑SIS‑tun‑YUR‑ee‑uh):
Genetic disorders are medical conditions that are passed down through families.

WHAT HAPPENS WHEN A PERSON HAS HOMOCYSTINURIA?

Homocystinuria causes levels of the amino acid homocysteine (HO-mo-SIS-teen) to build up in blood and urine. This build-up occurs when the body cannot properly process homocysteine or methionine (meh-THIGH-uh-neen), another amino acid. Amino acids are the building blocks that the body uses to make proteins. The cause of the buildup of homocysteine varies depending on the genetic disorder.

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

Watch this video to learn about why homocystinuria can occur in the body.

Learn more about the 3 types of genetic
disorders
that cause homocystinuria

Homocystinuria caused by
CBS deficiency
(classical homocystinuria)


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 makes too little CBS enzyme or none at all, or it makes CBS enzyme that does not work properly, levels of homocysteine and methionine (also an important amino acid) in the blood increase. The high levels of homocysteine cause harmful symptoms to develop.

 
Homocystinuria caused by MTHFR deficiency


Homocystinuria caused by 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency occurs when the body makes too little MTHFR enzyme or none at all, or it makes MTHFR enzyme that does not work properly. 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 this process does not occur as it should, blood levels of homocysteine increase and blood levels of methionine decrease. This causes harmful symptoms to develop.

Homocystinuria caused by cobalamin cofactor metabolism defect


Homocystinuria caused by cobalamin cofactor metabolism (cbl) defect 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.

Classical homocystinuria is divided into 3 subgroups:

  • People who respond to vitamin B6 (pyridoxine)
  • People who respond partially to vitamin B6
  • People who do not respond to vitamin B6. This group may have more severe symptoms.

What are the signs and symptoms of classical homocystinuria?

Classical homocystinuria 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;
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 classical homocystinuria 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.

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

How is classical homocystinuria diagnosed?

All states screen newborns for classical homocystinuria:

  • The screening tests for high methionine levels.
  • Newborn screening is not perfect and may not catch all newborns with the condition.
  • Some newborns with the condition may not have high methionine levels so soon after birth, and some premature newborns may not be developed enough for the screening to be accurate.
  • To learn more about newborn screening, visit babysfirsttest.org.

If someone has a positive newborn screen and/or symptoms that could be signs of classical homocystinuria, 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 classical homocystinuria 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 classical homocystinuria.

How is classical homocystinuria 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 vitamin B6 (pyridoxine) and additional B vitamins
  • Eating a low-protein diet
  • Taking a methionine-free amino acid formula
  • Taking CYSTADANE® (betaine anhydrous for oral solution) and other medicines

Always check with your doctor about what medicines,
vitamin supplements, and diet are right for you.

What are 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 may include:

Symbol of a brain

Behavioral or mental health problems

Symbol of a baby

Developmental delay or disability, such as being slow to roll over, sit up, walk or talk

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Movement or muscle problems

Symbol of a brain

Seizures

Symbol of arrows

Learning or memory problems

Symbol of a drop of blood

Trouble breathing

Symbol of a question mark

Lack of ability to stay awake, aware, or oriented to place and time

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

How is homocystinuria caused by MTHFR deficiency diagnosed?

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 MTHFR deficiency.

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 other therapies as directed by your doctor

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

What are the different types of cobalamin cofactor metabolist defects?

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, cblD variant 1, cblE, cblF, cblG, cblJ, and cblX.

By far the most common and best understood type of cbl defect 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. These are known as combined disorders.

Homocystinuria without methylmalonic acidemia occurs in people with cblD variant 1, cblE, or cblG defect. These are known as single disorders.

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.

Early-onset form of cblC defect

Most people with cblC defect develop signs and symptoms before they are a year old. This is the “early-onset” form of cblC defect. Symptoms that may develop include:

Symbol of eye
Vision symptoms, such as rapid, uncontrolled, or wandering/scanning eye movements
Symbol of brain
Small head and brain size (microcephaly)
Symbol of spinal chord
Symptoms related to the brain and spinal cord, such as seizures, drowsiness or lack of energy, or floppy muscles and joints
Symbol of bottle
Eating or growth problems, such as not wanting to nurse or take a bottle, or failure to grow and gain weight as expected
Symbol of lungs
Kidney blockages caused by damaged red blood cells
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Other symptoms involving the blood, heart, or lungs, such as anemia, heart disease, or blood clots
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Developmental delay or disability, such as being slow to sit up, walk, or talk

Late-onset form of cblC defect

People with a milder form of cblC defect may not develop symptoms until later in life—from childhood to adulthood. This is the “late-onset” form of cblC defect. Symptoms that may develop include:

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Blood clots

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Abnormal walking

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Muscle stiffness

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Learning problems

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Mental health problems

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

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

How is homocystinuria by cbl defect diagnosed?

Most states screen newborns for cbl defects with combined homocystinuria and methylmalonic acidemia, such as cblC and cblD, by looking for markers in the blood caused by high levels of methylmalonic acid (MMA). 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 a cbl defect, your doctor will order lab tests. These results may point to a positive diagnosis for most types of cbl defect, including cblC defect:

  • 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 cobalamin cofactor metabolism defect.

How is homocystinuria caused by cbl defect treated?

The goal of overall treatment is to prevent or lessen symptoms by keeping homocysteine, methionine, and methylmalonic acid (MMA) levels in your body as close to normal as possible. Treatment may include:

  • Getting injections of hydroxocobalamin (the only effective form of vitamin B12)
  • Taking CYSTADANE® (betaine anhydrous for oral solution)
  • Taking other therapies as directed by your doctor

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 a genetic disorder that causes 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 HCU Network America is to help people 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 activities.

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) defect

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.