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Glycine encephalopathy

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Other Names:
Hyperglycinemia nonketotic; Nonketotic hyperglycinemia; Glycine synthase deficiency; Hyperglycinemia nonketotic; Nonketotic hyperglycinemia; Glycine synthase deficiency; Non-ketotic hyperglycinemia See More
Glycine encephalopathy is an inherited metabolic disease characterized by abnormally high levels of an amino acid called glycine. Glycine is a chemical messenger that transmits signals in the brain.[1][2]  According to the symptoms the disease onset, glycine encephalopathy may be divided in:[3][2]
  • Classical neonatal form (most common): Symptoms start within a few days of life and may include poor feeding, lack of energy (lethargy), weak muscle tone (hypotonia), hiccups, breathing problems, seizures, hiccups, and coma.
  • Infantile form: Symptoms start only after 6 months of age, as intellectual disability, abnormal movements, and behavioral problems
  • Late onset: Symptoms include tightness or stiffness of the legs or arms (spastic diplegia), and vision loss due to a damage of the eye nerve (optic atrophy). 
  • Transient form: Symptoms are similar to the classic form, but glycine levels decrease and the symptoms may improve within time. 
Glycine encephalopathy is caused by changes (mutations) in the AMT, GLDC or GCSH genes which result in a deficiency of the enzyme that break-up the glycine. Diagnosis is based in the symptoms, the high glycine levels and the enzyme deficiency, as well as genetic testing.  Inheritance is autosomal recessive.[2][1] Treatment may include sodium benzoate to reduce the levels of glycine, N-methyl D-aspartate (NMDA) receptor site antagonists, anti-seizure drugs and ketogenic diet.[1] About half of the babies with the classic form, die within a few weeks of life and the survivors may have motor delay, very small head, seizures and stiffness. In the transient form symptoms may improve with time.[3]

 

Last updated: 11/18/2017
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.[4][2] Infants that survive this period typically have severe intellectual disability and seizures that are difficult to control.[4] 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.[2] 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.[2]

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.[2][4] 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.[2]
Last updated: 10/31/2011

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 28 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal metabolic brain imaging by MRS 0012705
Central hypotonia 0011398
EEG with burst suppression 0010851
Hyperglycinemia
Elevated blood glycine levels
0002154
Hypoplasia of the corpus callosum
Underdevelopment of part of brain called corpus callosum
0002079
Recurrent singultus
Recurrent hiccup
0100247
30%-79% of people have these symptoms
Breathing dysregulation 0005957
Generalized myoclonic seizure 0002123
Lethargy 0001254
Poor suck
Poor sucking
0002033
Respiratory acidosis 0005972
Percent of people who have these symptoms is not available through HPO
Agenesis of corpus callosum 0001274
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness
[ more ] 		0000718
Autosomal recessive inheritance 0000007
Death in infancy
Infantile death
Lethal in infancy
[ more ] 		0001522
Encephalopathy 0001298
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ] 		0001290
Hyperactivity
More active than typical
0000752
Hyperglycinuria
High urine glycine levels
0003108
Hyperreflexia
Increased reflexes
0001347
Hyporeflexia
Decreased reflex response
Decreased reflexes
[ more ] 		0001265
Impulsivity
Impulsive
0100710
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Irritability
Irritable
0000737
Muscular hypotonia
Low or weak muscle tone
0001252
Myoclonus 0001336
Restlessness 0000711
Seizure 0001250
Showing of 28 |
Last updated: 7/1/2020
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.[5] 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.
Last updated: 10/28/2011
Currently there is not a cure for glycine encephalopathy.[1][6] 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.[1]

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.[1]  Drug dosage must be individually tailored and requires regular and careful monitoring.[1][6] Studies regarding the effectiveness of these treatments are ongoing.[1] Mildly affected individuals may receive the greatest benefit from treatment, particularly if treatment is started early.[1]

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.[1]

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.
http://www.ncbi.nlm.nih.gov/books/NBK1357/#nkh.Management

Last updated: 11/10/2011
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.[4]
Last updated: 10/31/2011

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes organic acidemias that may present hyperglycinemia such as D-glyceric acidemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms). Conditions characterized by neonatal seizures should also be considered. Valproate treatment may cause hyperglycinemia.
Visit the Orphanet disease page for more information.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Glycine encephalopathy. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • 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.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Glycine encephalopathy. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • My granddaughter has just been diagnosed with glycine encephalopathy. She is 3 months old. All the articles we have read are very complicated. What is glycine encephalopathy about? What treatment is there and what are her survival chances? See answer

  • Is it necessary to restrict protein intake in children that have this disorder? If so, what are the risks if protein intake is not restricted? See answer

  • My son has NKH and is my first born child. What is the chance my next child will have NKH if he has a different father? See answer


  1. Hamosh A, Scharer G, Van Hove J. Glycine encephalopathy. GeneReviews. 2013; http://www.ncbi.nlm.nih.gov/books/NBK1357/.
  2. Glycine encephalopathy. Genetics Home Reference. April 2007; http://ghr.nlm.nih.gov/condition/glycine-encephalopathy.
  3. Iqbal M, Prasad M & Mordekar SR. Nonketotic hyperglycinemia case series. Journal of Pediatric Neurosciences. 2015; 10(4):355-358. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770648/.
  4. Ada Hamosh, Gunter Scharer, Johan Van Hove. Glycine Encephalopathy. GeneReviews. July 11, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1357/. Accessed 6/9/2015.
  5. Glycine encephalopathy. Genetics Home Reference Website. April 2007; http://ghr.nlm.nih.gov/condition=glycineencephalopathy. Accessed 10/7/2008.
  6. Van Hove JL, Vande Kerckhove K, Hennermann JB, Mahieu V, Declercq P, Mertens S, De Becker M, Kishnani PS, Jaeken J. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia. J Inherit Metab Dis. 2005;28(5):651-63; http://www.ncbi.nlm.nih.gov/pubmed/16151895. Accessed 8/26/2011.