Nonketotic hyperglycinemia is a disorder characterized by abnormally high levels of a molecule called glycine in the body (hyperglycinemia). The excess glycine builds up in tissues and organs, particularly the brain. Affected individuals have serious neurological problems.

Nonketotic hyperglycinemia has two forms, the severe form and the attenuated form. Both forms usually begin shortly after birth, although in some cases, signs and symptoms can begin in the first few months of life. Only the attenuated form begins later in infancy. The forms are distinguished by the seriousness of the signs and symptoms. Severe nonketotic hyperglycinemia is more common. Affected babies experience extreme sleepiness (lethargy) that worsens over time and can lead to coma. They can also have weak muscle tone (hypotonia) and life-threatening breathing problems in the first days or weeks of life. Most children who survive these early signs and symptoms develop feeding difficulties, abnormal muscle stiffness (spasticity), profound intellectual disability and seizures that are difficult to control. Most affected children do not achieve normal developmental milestones, such as drinking from a bottle, sitting up, or grabbing objects, and they may lose any acquired skills over time.

The signs and symptoms of the attenuated form of nonketotic hyperglycinemia are similar to, but milder than, those of the severe form of the condition. Children with attenuated nonketotic hyperglycinemia typically reach developmental milestones, although the skills they achieve vary widely. Despite delayed development, many affected children eventually learn to walk and are able to interact with others, often using sign language. Some affected children develop seizures; if present, seizures are usually mild and can be treated. Other features can include spasticity, involuntary jerking movements (chorea), or hyperactivity.

Individuals with nonketotic hyperglycinemia can also have certain changes in the brain, which can be seen using magnetic resonance imaging (MRI). For example, in children with the severe form of the condition, the tissue that connects the left and right halves of the brain (the corpus callosum) is smaller than average.

Mutations in the GLDC or AMT gene cause nonketotic hyperglycinemia. About 80 percent of cases result from mutations in the GLDC gene, while AMT gene mutations cause about 20 percent of all cases.

The GLDC and AMT genes provide instructions for making enzymes that work together as a group. This group, known as the glycine cleavage system, is responsible for breaking down glycine into smaller pieces when it is no longer needed. Glycine is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Too much glycine can disrupt brain function.

In addition, the breakdown of glycine by the glycine cleavage system produces a molecule called a methyl group. This molecule is added to and used by a vitamin called folate. Folate is required for many functions in the cell and is important for brain development.

Mutations in either the GLDC or AMT gene impair the system's ability to break down glycine. Some mutations reduce the activity of the glycine cleavage system, while others completely eliminate its activity. When the function of the glycine cleavage system is disrupted, excess glycine can build up in the body's organs and tissues. In addition, the production of methyl groups for use by folate is reduced. It is unclear how these abnormalities contribute to the developmental disability, seizures, breathing difficulties, and other features characteristic of nonketotic hyperglycinemia.

The activity level of the glycine cleavage system helps determine the severity of the disorder: GLDC or AMT gene mutations that completely eliminate the system's activity result in severe nonketotic hyperglycinemia, while mutations that preserve some activity cause attenuated nonketotic hyperglycinemia.

Normal Function

The GLDC gene provides instructions for making an enzyme called glycine dehydrogenase. This protein is one of four enzymes that work together in a group called the glycine cleavage system. Within cells, this system is active in specialized energy-producing centers called mitochondria.

As its name suggests, the glycine cleavage system breaks down a molecule called glycine by cutting (cleaving) it into smaller pieces. Glycine is an amino acid, which is a building block of proteins. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. The breakdown of excess glycine when it is no longer needed is necessary for the normal development and function of nerve cells in the brain.

The breakdown of glycine by the glycine cleavage system produces a molecule called a methyl group. This molecule is added to and used by a vitamin called folate. Folate is required for many functions in the cell and is important for brain development.

Health Conditions Related to Genetic Changes

Nonketotic hyperglycinemia

Mutations in the GLDC gene account for about 80 percent of all cases of nonketotic hyperglycinemia. This condition is characterized by abnormally high levels of glycine in the body (hyperglycinemia). Affected individuals have serious neurological problems. The signs and symptoms of the condition vary in severity and can include severe breathing difficulties shortly after birth as well as weak muscle tone (hypotonia), seizures, and delayed development of milestones. More than 400 mutations have been identified in affected individuals. Many of these genetic changes alter single amino acids in glycine dehydrogenase. Other mutations insert or delete genetic material in the GLDC gene, or disrupt how genetic information from the gene is spliced together to make a blueprint for producing glycine dehydrogenase.

Some GLDC gene mutations lead to the production of a nonfunctional version of glycine dehydrogenase, while other mutations reduce but do not eliminate the enzyme's activity. When an altered version of this enzyme is incorporated into the glycine cleavage system, it impairs the system's ability to break down glycine. As a result, excess glycine can build up in the body's organs and tissues. In addition, the production of methyl groups for use by folate is reduced. It is unclear how these abnormalities contribute to the developmental disability, seizures, breathing difficulties, and other features characteristic of nonketotic hyperglycinemia.

Other Names for This Gene

• GCE
• GCSP
• GCSP_HUMAN
• glycine cleavage system protein P
• glycine decarboxylase P-protein
• glycine dehydrogenase (decarboxylating)
• glycine dehydrogenase (decarboxylating; glycine decarboxylase, glycine cleavage system protein P)
• NKH

Genomic Location

Normal Function

The AMT gene provides instructions for making an enzyme called aminomethyltransferase. This protein is one of four enzymes that work together in a group called the glycine cleavage system. Within cells, this system is active in specialized energy-producing centers called mitochondria.

As its name suggests, the glycine cleavage system breaks down a molecule called glycine by cutting (cleaving) it into smaller pieces. Glycine is an amino acid, which is a building block of proteins. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. The breakdown of excess glycine when it is no longer needed is necessary for the normal development and function of nerve cells in the brain.

The breakdown of glycine by the glycine cleavage system produces a molecule called a methyl group. This molecule is added to and used by a vitamin called folate. Folate is required for many functions in the cell and is important for brain development.

Health Conditions Related to Genetic Changes

Nonketotic hyperglycinemia

Mutations in the AMT gene account for about 20 percent of all cases of nonketotic hyperglycinemia. This condition is characterized by abnormally high levels of glycine in the body (hyperglycinemia). Affected individuals have serious neurological problems. The signs and symptoms of the condition vary in severity and can include severe breathing difficulties shortly after birth as well as weak muscle tone (hypotonia), seizures, and delayed development of milestones. More than 70 mutations have been identified in affected individuals. Most of these genetic changes alter single amino acids in aminomethyltransferase. Other mutations delete genetic material from the AMT gene or disrupt how genetic information from the gene is spliced together to make a blueprint for producing aminomethyltransferase.

AMT gene mutations alter the structure and function of aminomethyltransferase. When an altered version of this enzyme is incorporated into the glycine cleavage system, it impairs the system's ability to break down glycine. Some AMT gene mutations reduce the activity of the glycine cleavage system, while others completely eliminate its activity. As a result, excess glycine can build up in the body's organs and tissues. In addition, the production of methyl groups for use by folate is reduced. It is unclear how these abnormalities contribute to the developmental disability, seizures, breathing difficulties, and other features characteristic of nonketotic hyperglycinemia.

Other Names for This Gene

• GCE
• glycine cleavage system protein T
• NKH

Genomic Location

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

• NKH is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes NKH (GLDC or AMT) to their baby. Only babies with two matching nonworking genes—for example, one nonworking GLDC from the mom and one nonworking GLDC from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking GLDC from the mom and one nonworking AMT from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the GLDC or AMT 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 GLDC or AMT gene, they have a 1 in 4 chance of having a child with NKH.
  • Carriers for NKH 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 NKH.
  • Parents who already have a child with NKH still have a 1 in 4 chance of having another child with NKH. 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.

Signs of NKH are typically present shortly after birth. In some cases, signs and symptoms show up a little later in infancy.

Signs of the condition may include the following:

• Sleepiness or lack of energy (lethargy)
• Weak muscle tone (hypotonia)
• Breathing trouble
• Trouble feeding
• Seizures
• Coma
• Developmental delay
• Muscle stiffness (spasticity)

Newborn screening for NKH requires collecting a small amount of blood from your baby’s heel. Screening measures how much glycine is in your baby’s blood. Babies with high levels of glycine might have NKH.

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

If your baby’s blood spot screening result for NKH 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 soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. Babies who have severe liver problems or low oxygen in their brain may have false positive results for NKH.

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.

It is important to talk to your health care provider about how to best care for your baby. Currently, the treatment options available cannot stop the progression of the condition. Health care providers will develop a plan that is tailored to the needs of each child.

Nonketotic hyperglycinemia is estimated to affect at least 1 in 76,000 people worldwide. In Finland, the condition occurs in about 1 in 55,000 newborns, and in British Columbia, Canada, it occurs in about 1 in 63,000 newborns.