Homocystinuria causes levels of the amino acid homocysteine (HO-mo-SIS-teen) to buildup in blood and urine. This buildup 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.
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 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 (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 can affect many parts of the body:
Learning problems and
developmental delays, such as
being slow to sit up, walk, or talk
Problems with the lenses in the
eyes, such as lens dislocation;
nearsightedness (often severe);
quivering of the iris (the colored
part of the eye)
Tall, thin body with long arms, legs, fingers and toes; curved spine; osteoporosis (brittle or weak bones)
Development of blood clots
All states screen newborns for classical homocystinuria:
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:
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.
The overall goal of treatment is to prevent or lessen symptoms by reducing the level of homocysteine in the blood.
Treatment may include:
Symptoms of homocystinuria caused by severe MTHFR deficiency can begin in infancy or
early childhood. Symptoms may include:
Behavioral or mental health problems
Developmental delay or disability, such as being slow to roll over, sit up, walk or talk
Movement or muscle problems
Learning or memory problems
Lack of ability to stay awake, aware, or oriented to place and time
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:
Genetic testing can confirm the diagnosis.
The overall goal of treatment is to lessen symptoms by reducing the level of homocysteine and maintaining a normal level of methionine in the blood. Treatment may include:
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.
Symptoms of homocystinuria caused by cblC defect can develop for the first time at any age and can vary greatly from person to person.
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:
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:
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.
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:
Genetic testing can confirm the diagnosis.
The overall goal of 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:
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
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
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.
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.
CYSTADANE (betaine anhydrous for oral solution) is indicated in children and adults 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: