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.
This short video explains the different causes of Homocystinuria, how it effects the body, and how it can be treated.
We will cover the chemical processes in the body that form Homocysteine. The enzyme deficiencies that lead to Homocystinuria, and how Homocystinuria can be treated.
When you eat foods such as meat, fish, eggs, or cheese, your body takes in an amino acid called Methionine. Your body then metabolizes or breaks down Methionine into another amino acid called Homocysteine.
If your body cannot properly break down Homocysteine into other amino acids, Homocysteine can build up in your blood.
This route map shows the processes involved in Homocysteine metabolism or how the body breaks down Homocysteine. Methionine is converted by the body to Homocysteine, represented here, by the blue cars changing to purple cars. Homocysteine levels are controlled by three pathways; the Transsulfuration Pathway, the Folate-Dependent Remethylation Pathway, and the Folate Non-dependent Remethylation Pathway. The combined activity of these pathways determines the levels of Homocysteine and cells, and the blood stream. High levels of Homocysteine lead to Homocystinuria which is harmful to the body. Normally the routes run smoothly, but in Homocystinuria, enzyme deficiencies can block a pathway and cause a dangerous buildup of Homocysteine. Now let's look at how this can occur.
The first and main route of Homocysteine metabolism is the Transsulfuration Pathway which converts Homocysteine into Cysteine, another amino acid. Cysteine is represented by the white cars.
This process depends on the enzyme, CBS, represented here by a car wash. CBS is helped by Vitamin B6, represented here as the nozzle. When the car wash malfunctions, and the pathway becomes blocked, the conversion of Homocysteine to Cysteine is impaired, leading to a buildup of Homocysteine. This is known as Homocystinuria due to CBS Deficiency or Classical Homocystinuria.
Classical Homocystinuria is divided into two types; Vitamin B6 responsive and Vitamin B6 non-responsive. This will be discussed more later.
The second route of Homocysteine metabolism is the Remethylation Pathway that depends on Folate, a B vitamin. This pathway converts Homocysteine back to Methionine. This conversion depends on the enzyme, MTHFR, represented here by the paint supplying the paint spray unit. When there's no paint in the drum, the paint spray can't function, causing the cars - or Homocysteine - to back up. This type of Homocystinuria is known as MTHFR Deficiency, a second enzyme Methionine Synthase or MS, is represented here by the barrier. MS is also needed to convert Homocysteine back to Methionine. Defects in the metabolism of Cobalamin, also known as B12, can cause the MS enzyme to malfunction. If this happens, the barrier cannot function and cars cannot enter the paint spray, again causing the cars or Homocysteine to back up. This type of Homocystinuria is known as a Colbalamin Co-factor Metabolism Defect or CBL Defect which includes many different subtypes.
The third pathway controlling Homocysteine levels is the Folate Non-dependent Remethylation Pathway. Remethylation of Homocysteine is represented by a second paint spray unit. This pathway depends on Betaine which occurs naturally in the body when small amounts of it are ingested from certain foods. However, depending on the amount of Betaine in the body, this pathway can get overwhelmed, and becomes jammed with traffic if other pathways are blocked.
If any of these pathways is not functioning correctly, Homocysteine levels within cells rise and Homocysteine is released into the blood.
Homocystinuria can have serious harmful effects on the body depending on the type of Homocystinuria. Symptoms may include eye and vision problems, blood clots, bone problems such as weak bones, or problems with the brain that effect learning, growth and development.
The treatment of Homocystinuria varies depending on the type. The goal of treatment is to decrease high Homocysteine blood levels to prevent or reduce further harm to the body.
We'll talk first about treatment for people with CBS Deficiency or Classical Homocystinuria.
Vitamin B6 supplements are very important for people who are responsive to Vitamin B6. Shown here, Vitamin B6 can activate the CBS car wash and reduce the build-up of Homocysteine by converting Homocysteine to Cysteine.
However, Vitamin B6 supplements are not effective for people who are not responsive to Vitamin B6.
Most people who are non-responsive to Vitamin B6, must follow a Methionine restricted diet that's very low in protein. This helps reduce the intake of Methionine and helps reduce the build-up of Homocysteine. Other B vitamins, Folate, and/or Vitamin B12 may be included in treatment regardless of responsiveness to Vitamin B6.
For people with a CBL Defect, Vitamin B12 injections are an important part of treatment.
As shown here, when the MS enzyme is not functioning properly, cars cannot enter the paint spray and they get backed up. When the Vitamin B12 switch is turned on, the MS barrier can move again, allowing the cars to enter the paint spray unit, reducing the build-up of Homocysteine.
CYSTADANE® (betaine anhydrous for oral solution) is indicated in children and adults for the treatment of Homocystinuria to decrease high Homocysteine blood levels. The following are considered to be Homocystinuria disorders: CBS Deficiency, MTHFR Deficiency, CBL Defect. As shown here, CYSTADANE® can help with the Folate Non-Dependent Remethylation Pathway. The addition of CYSTADANE® increases the performance of the paint spray unit to convert more Homocysteine back to Methionine; the cars move faster through the paint spray unit and the build-up of Homocysteine cars is thereby reduced.
Hypermethioninemia in Patients with CBS Deficiency: CYSTADANE® may worsen high Methionine blood levels and accumulation of excess fluid in the brain has been reported. If you've 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.
The recommended dose of CYSTADANE® in adults and children 3 years and older is 3 grams twice a day. In children younger than 3 years, the dose may start at 50 milligrams per kilogram twice a day and then be increased weekly by 50 milligrams per kilogram.
CYSTADANE® is the only FDA approved Betaine Anhydrous prescription medication that is indicated for the treatment of Homocystinuria to decrease high Homocysteine blood levels. CYSTADANE® is manufactured according to the high quality and consistency standards required for prescription drugs. CYSTADANE® contains only Betaine Anhydrous which is Betaine in powder form. There are no other ingredients. Financial assistance programs are available to help eligible patients.
Important Safety Information: Hypermethioninemia in patients with CBS Deficiency: CYSTADANE® may worsen high Methionine blood levels and accumulation of excess fluid in the brain has been reported. 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
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: