Nonketotic Hyperglycinemia

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Nonketotic Hyperglycinemia

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Glycine encephalopathy

overview Question

What is glycine encephalopathy?

Glycine encephalopathy is an inherited condition characterized by abnormally high levels of an amino acid called glycine. Glycine acts as a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body, thus allowing excess glycine to build up in tissues and organs, particularly the brain. Symptoms typically appear during infancy or early childhood and include a lack of energy (lethargy), feeding difficulties, weak muscle tone (hypotonia), abnormal jerking movements, breathing problems, seizures, and intellectual disability. It is caused by mutations in the AMT, GLDC or GCSH genes and is inherited in an autosomal recessive manner.

Date Modified: 2011-11-10T10:41:00

basic Questions

What are the signs and symptoms of glycine encephalopathy?

Most individuals with glycine encephalopathy begin to show signs and symptoms in the first hours or first days of life (the neonatal period). Of these affected individuals, approximately 85% have a neonatal severe form, and 15% have a neonatal mild form. The signs and symptoms often include progressive lack of energy (lethargy), feeding difficulties, poor muscle tone (hypotonia), abnormal jerking movements (myoclonic jerking) and life-threatening breathing problems such as apnea. Infants that survive this period typically have severe intellectual disability and seizures that are difficult to control. Affected males are more likely to survive and tend to have more mild developmental problems than affected females, although the reason for this is unclear. In rare instances, the main features of the condition improve with time; in these cases, the condition is known as transient glycine encephalopathy because glycine decreases to normal or near-normal levels after being very high at birth. Many children with the transient form will develop normally and experience few long-term medical problems, but some individuals may continue to have intellectual disability or seizures even after glycine levels decrease.

There have been affected individuals with "atypical" forms of the condition with variable signs and symptoms; these forms have ranged from milder disease with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset. The most common "atypical" form is known as the infantile form and is characterized by hypotonia, developmental delay and seizures. Individuals with this form may develop normally until signs and symptoms begin at approximately 6 months of age. As they age, many of these individuals develop intellectual disability, abnormal movements and behavioral problems. Other atypical forms of glycine encephalopathy can appear later in childhood or adulthood and cause a variety of medical problems that primarily affect the nervous system.

Date Modified: 2011-10-31T10:02:00

How is glycine encephalopathy inherited?

Glycine encephalopathy is inherited in an autosomal recessive pattern, which means in an affected individual, both copies of the gene that cause this condition have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene and are referred to as carriers. Carriers typically do not show signs and symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Date Modified: 2011-10-28T10:37:00

How might glycine encephalopathy be treated?

Currently there is not a cure for glycine encephalopathy. All but very mildly or atypically affected individuals develop intellectual disability and seizures, even with treatment. Treatment options for people with glycine encephalopathy may vary depending on the severity of their condition. Tests, such as MRI and EEG, as well as evaluations of development and neurological function can help determine the severity of the condition in an infant, child, or adult.

The goal of treatment is to reduce the amount of glycine in the plasma (blood). Treatment may involve a medication called sodium benzoate, which binds with glycine allowing it to be passed out in the urine, and dextromethorphan, ketamine, or felbamate, which block some of the harmful effects of excessive glycine. These treatments may help control seizures, increase alertness, and in mildly affected individuals, improve behavior.  Drug dosage must be individually tailored and requires regular and careful monitoring. Studies regarding the effectiveness of these treatments are ongoing. Mildly affected individuals may receive the greatest benefit from treatment, particularly if treatment is started early.

Other treatments include drugs to control seizures (anti-epileptic drugs); assistive devices or surgeries to aid with feeding and swallowing (e.g., gastrostomy tube); physical therapy; and scoliosis management. Parents and family members may benefit from genetic counseling. Click here to learn more about genetic consultations.

For further details on treatment, please visit the following link to GeneReviews. GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions. Because of the complexity of the information in the article, we recommend that you review it with a health care provider.

Date Modified: 2011-11-10T10:24:00

What is the prognosis for individuals with glycine encephalopathy?

The prognosis and chance of survivial for an individual affected with glycine encephalopathy depend on the form of the condition the individual has as well as complications that may arise. Preliminary data suggest that the specific mutations that an individual has can somewhat be used to predict the outcome of the disease. Mutations associated with residual enzyme activity (some functioning enzyme present) seem to be associated with a mild outcome, and two known mutations with no residual enzyme activity (no working enzyme present) seem to be associated with a severe outcome. However, because many mutations are "private" (only present in a single family) and some affected individuals die before their outcome is known, it is difficult to predict the outcome for many individuals. The best outcome ever reported is normal intelligence, which has only been seen in individuals who do have some functioning enzyme activity and have had early and aggressive treatment in the first two years of life.

About 85% of individuals affected in the neonatal period (first hours to days of life) have a severe form, and 15% have a mild form. Of the individuals who begin to have signs and symptoms in infancy (the infantile form), about 50% have a severe form and 50% have a mild form. Overall, about 20% of all infants with the neonatal or infant form have a mild outcome. Occasionally, affected individuals have an intermediate outcome between mild and severe.

Individuals with a mild form of the disease can have variable degrees of developmental progress; they may learn to walk, interact with others and attend special education classes. One study found that up to 20% of surviving children learn to walk and say or sign words. These individuals may have little spasticity and they often develop a treatable seizure disorder.

Individuals with a severe form typically do not make developmental progress. At most, they may learn to sit and have very limited interaction with their environment. During the first year of life, they typically develop seizures that become increasingly difficult to treat, usually requiring multiple anticonvulsant medications. They typically have progressive spasticity early on, they have a tendency to develop scoliosis, and they often have swallowing dysfunction that requires tube feeding.

Date Modified: 2011-10-31T10:41:00


Agenesis of corpus callosum

Aggressive behavior

Autosomal recessive inheritance

Death in infancy







Intellectual disability



Muscular hypotonia


Recurrent singultus