Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body.

People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.

Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia, and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula. The condition is called primary hypermethioninemia when it is not associated with other metabolic disorders or excess methionine in the diet.

Primary hypermethioninemia that is not associated with other metabolic disorders can be caused by variants (also known as mutations) in the MAT1A, GNMT, or AHCY gene. These genes provide instructions for making enzymes that each carry out one step of the multistep process to break down methionine. The reactions involved help supply some of the amino acids needed for protein production. These reactions are also involved in transferring methyl groups, consisting of a carbon atom and three hydrogen atoms, from one molecule to another (transmethylation), which is important in many cellular processes.

The MAT1A gene provides instructions for producing the enzyme methionine adenosyltransferase. This enzyme converts methionine into a compound called S-adenosylmethionine, also known as AdoMet or SAMe.

The GNMT gene provides instructions for making the enzyme glycine N-methyltransferase. This enzyme starts the next step in the process, converting AdoMet to a compound called S-adenosyl homocysteine (also known as AdoHcy).

The AHCY gene provides instructions for producing the enzyme S-adenosylhomocysteine hydrolase. This enzyme converts AdoHcy into the compound homocysteine. Homocysteine may be converted back to methionine or into another amino acid, cysteine.

Variants in one of these genes result in a shortage (deficiency) of an enzyme involved in breaking down methionine. A deficiency of any of these enzymes leads to a buildup of methionine in the body, which may cause signs and symptoms related to hypermethioninemia.

Hypermethioninemia is a genetic condition. Babies inherit it from their biological (birth) parents.

• Most of the time, hypermethioninemia is an autosomal recessive condition. Babies inherit it when each parent passes down the same nonworking gene that causes hypermethioninemia (AHCY, GNMT, or MAT1A) to their baby. Only babies with two matching nonworking genes—for example, one nonworking ACHY from the mom and one nonworking ACHY from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking ACHY from the mom and one nonworking GNMT from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the AHCY, GNMT, or MAT1A gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children. If two parents are carriers of a nonworking copy of the AHCY, GNMT, or MAT1A gene, they have a 1 in 4 chance of having a child with hypermethioninemia.
  • Carriers for hypermethioninemia often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with hypermethioninemia.
  • Parents who already have a child with hypermethioninemia have a 1 in 4 chance of having another child with hypermethioninemia. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Although most people with hypermethioninemia do not show any signs, some people with the condition do show signs. Signs can result from eating foods the body cannot break down properly, illness, infection, or a long time without food.

Signs of the condition may include the following:

• Delays in development
• Sleeping longer or more often (lethargy)
• Weak muscle tone (hypotonia)
• A “cabbage-like” smell
• Liver problems
• Unusual facial features

Newborn screening for hypermethioninemia is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much methionine is in your baby’s blood. Babies with high levels of this substance might have hypermethioninemia.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for hypermethioninemia is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. However, the following situations can affect screening results:

• Babies on supplemental nutrition (also called total parenteral nutrition, or TPN)
• Babies who were born early (premature)

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

Most children with hypermethioninemia do not need treatment. It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Restricted diet that avoids food with methionine
• Special foods or formulas

Primary hypermethioninemia that is not caused by other disorders or excess methionine intake appears to be rare; only a small number of cases have been reported. The actual incidence is difficult to determine, however, since many individuals with hypermethioninemia have no symptoms.