Cookies help us deliver our services. By using our services, you agree to our use of cookies. Learn more

Non-Ketotic Hyperglycinemia

What is Non-Ketotic Hyperglycinemia?

Non-ketotic hyperglycemia (NKH) is caused by the disruption of glycine breakdown. Glycine is an amino acid, which is a building block of proteins. In NKH, the enzyme that degrades glycine is dysfunctional, leading to an accumulation of this molecule in body tissues, including the brain. Glycine is also a neurotransmitter. Neurotransmitters are molecules that are responsible for signal transmission between nerve cells. As a result, high levels of glycine has particularly significant effects on brain function.

The most common type of NKH is the classic form which presents shortly after birth. Depending on the time of onset and clinical outcome, the classic form can be classified as neonatal severe, neonatal attenuated, infantile attenuated, and infantile severe. Attenuated forms have milder symptoms and better outcomes.

The neonatal form manifests as lack of energy (lethargy), lack of muscle tone or resistance to stretch in muscle (hypotonia), sudden muscle contractions (myoclonic jerks) leading to the temporary inability to breathe (apnea) and even death. Significant intellectual disability and seizures that are difficult to treat may occur in surviving infants. Intractable seizures are seizure disorder which can not be controlled with treatment.  The infantile form usually does not exhibit symptoms until 6 months of age and is defined by hypotonia, developmental delay, and seizures.

In atypical cases, NKH may develop later in infancy or even adulthood and may have milder symptoms or rapidly progressive and severe symptoms. Rarely, symptoms of NKH may improve over time where glycine levels decrease to near-normal. This is known as transient NKH and many affected individuals develop normally with few long-term complications.

 

 

Synonyms

  • Non-ketotic hyperglycinemia
  • Non-ketotic hyperglycinemia
  • Glycine encephalopathy

Non-ketotic hyperglycemia (NKH) is caused by the disruption of glycine breakdown. Glycine is an amino acid, which is a building block of proteins. In NKH, the enzyme that degrades glycine is dysfunctional, leading to an accumulation of this molecule in body tissues, including the brain. Glycine is also a neurotransmitter. Neurotransmitters are molecules that are responsible for signal transmission between nerve cells. As a result, high levels of glycine has particularly significant effects on brain function.

The most common type of NKH is the classic form which presents shortly after birth. Depending on the time of onset and clinical outcome, the classic form can be classified as neonatal severe, neonatal attenuated, infantile attenuated, and infantile severe. Attenuated forms have milder symptoms and better outcomes.

The neonatal form manifests as lack of energy (lethargy), lack of muscle tone or resistance to stretch in muscle (hypotonia), sudden muscle contractions (myoclonic jerks) leading to the temporary inability to breathe (apnea) and even death. Significant intellectual disability and seizures that are difficult to treat may occur in surviving infants. Intractable seizures are seizure disorder which can not be controlled with treatment.  The infantile form usually does not exhibit symptoms until 6 months of age and is defined by hypotonia, developmental delay, and seizures.

In atypical cases, NKH may develop later in infancy or even adulthood and may have milder symptoms or rapidly progressive and severe symptoms. Rarely, symptoms of NKH may improve over time where glycine levels decrease to near-normal. This is known as transient NKH and many affected individuals develop normally with few long-term complications.

 

Acknowledgement of Non-Ketotic Hyperglycinemia has not been added yet.

The worldwide incidence of NKH is unknown. However, it has been studied in certain regions of the world. The birth incidence of NKH is 1:55,000 in Finland, 1:12,000 in an area of Northern Finland, and 1:63,000 in British Columbia, Canada.

Name Abbreviation
Non-ketotic hyperglycinemia Hyperglycinemia, Nonketotic
Non-ketotic hyperglycinemia NKH
Glycine encephalopathy Gycine encephalopathy

NKH is caused by a deficiency in what is known as the glycine cleavage enzyme system (GCS or GCE). The GCS is an enzyme complex, responsible for breaking down glycine into smaller molecules. An enzyme complex is a collection of proteins that work together to speed up chemical reactions in the body, such as the breakdown of a large molecule into smaller products. The GCS is made up of four distinct proteins known as P-protein (pyridoxal phosphate containing glycine decarboxylase, GLDC), H-protein (lipoic acid containing), T-protein (tetrahydrofolate-requiring aminomethyltransferase, AMT), and L-protein (lipoamide dehydrogenase). 80% of affected individuals have a defective P-protein while 15% have a defective T-protein. H-protein defects rarely occur in NKH and L-protein defects are associated with a distinct condition. Each of these proteins is encoded by different genes. The P-protein is encoded by a gene known as GLDC, T-protein is encoded by a gene known as AMT, and H-protein is encoded by a gene known as GCSH. Mutations in these genes are responsible for the deficiency in their corresponding proteins, and thus, NKH. Although, in 5% of cases have both genes are normal and the underlying cause of the condition is unknown. NKH is an autosomal recessive disorder. Everyone receives one copy for each gene from their mother and one copy from their father. An autosomal recessive disorder means that both copies of the gene must be defective for NKH to present.

Mutations in either the AMT, GLDC, or GCSH genes leads to a glycine cleavage enzyme complex that is unable to breaking down glycine properly. As a result, glycine will build up in the body, causing damage to the brain and spinal cord, in particular, followed by intellectual disability, seizures, and breathing difficulties.

 

Symptoms of NKH vary depending on the onset and the severity of NKH. Importantly, NKH symptoms present as a continuous spectrum and may fall between the forms described here. In most affected individuals present NKH as neonates, out of which 85% develop the severe form and 15% develop the attenuated form. In individuals affected by the neonatal form, symptoms are observed within the first hours or days after birth. Symptoms include progressive lack of energy (lethargy), lack of muscle tone or resistant to stretch in muscle(hypotonia), sudden and involuntary muscle contraction (myoclonic jerks) which can lead to the temporary inability to breath (apnea), coma, and even death of untreated. Involuntary muscle contractions lead to apnea as muscles involved in breathing can also get involved. Affected individuals may need intubation and mechanical ventilation to facilitate breathing. Intubation refers to the placement of a flexible tube into the airways. A mechanical ventilation machine will then breathe for the affected individual through their intubation. It is important to note that the vast majority of affected individuals will regain their ability to breathe in a few weeks. Further intellectual disabilities and seizures may develop. Other less common symptoms and findings in the neonatal severe form includes potential brain malformation, cleft lip/palate, and malformed ears.

A smaller percentage of affected individual may present symptoms in infancy, out of which 50% develop the severe form and 50% develop  the attenuated form. There are differences between the infantile and the neonatal forms. Individuals affected by the infantile form do not exhibit the lack of energy (lethargy) and apnea observed in the neonatal form. However, they may have a history of low muscle tone or hypotonia. Muscle tone is the unconscious and low level of muscle contraction when they are at rest. Hypotonia is commonly known as the floppy baby syndrome as the affected infant’s muscles may feel abnormally soft or limp. The infantile form also presents with developmental delay and infantile-onset seizures.

Additionally, as described earlier, the severity of the condition plays a role in symptom presentation. Individuals who develop the severe form, have significant developmental delay. They may learn to smile, grasp objects, or sit and present with seizures that become more difficult to treat as they age. Other complications could be scoliosis which is the sideway curvature of the spine, as well as difficulty swallowing. Many affected individuals may develop what is known as spastic quadriparesis. This is a condition affecting all four limbs that is characterized by stiffness and muscle contraction that makes it difficult to move. In rare cases, club feet has also been found. Club feet describes a conditions where the feet are rotated inwards or downwards and the soles of the feet face each other.

 

Individuals who develop the attenuated form have less severe developmental delay but tend to be hyperactive. They are likely to learn to walk, interact with caregivers, have sign language, and attend special education classes. Seizures are still common but are easily treated.  They may exhibit choreic movement which is an abnormal, quick, and involuntary movement of the hands and feet. However, this has been associated with better prognostic outcome. Furthermore, episodes of severe lethargy might occur in these individuals.

There have been rare reports of individuals who develop a mild form of the condition. They have some developmental disability and may be able to attend normal schooling. They may or may not have seizures and could have  attention deficit and hyperactivity disorder (ADHD).


NKH may present as an atypical form that could range from mild symptoms presenting in late infancy to adulthood, to late-onset rapidly progressing severe form.

 

Name Description
Listlessness Listlessness
Spasticity Spasticity
Seizures Seizures
Involuntary muscle contractions Involuntary muscle contractions
Opisthotonos Opisthotonos
Hiccups Hiccups
Apnea Apnea
Failure to thrive Failure to thrive
Mental retardation Mental retardation
Progressive spastic diplegia Progressive spastic diplegia in late onset form
Optic atrophy Optic atrophy in late onset form
Convulsions Convulsions
Poor feeding Poor feeding
Vomiting Vomiting
High level of glycine High level of glycine in urine, in plasma, and in cerebrospinal fluid.
Reduced muscle tone Reduced muscle tone

NKH is suspected when CSF glycine concentration, as well as the CSF-to-plasma glycine ratio is elevated. CSF, or the cerebrospinal fluid, is a fluid surrounding the brain and in the spinal cord that plays that protects these vital structures. Diagnosis is confirmed through a biopsy that shows diminished enzymatic activity of the glycine cleavage system in the liver. Affected individual often have no detectable enzymatic activity.

When NKH is clinically suspected, biochemical screening must be performed to measure the level of glycine in both plasma and CSF. If glycine levels are elevated in plasma and CSF, further confirmatory tests will be performed.

Genetic testing could further support diagnosis. Certain variations in GLDC, AMT, and GCSH genes are known to cause NKH. Commonly, all three genes are sequenced concurrently to identify possible genetic disease-causing variations.  

Finally, diagnosis can be confirmed using enzymatic measurement of glycine cleavage system in the liver. The liver tissue required for biopsy is obtained endoscopically. This procedure is a non-surgical technique where a thin flexible tube is used to obtain the sample required.

Measurement of glycine cleavage system enzymatic activity is the confirmatory diagnostic test for NKH.

 

The current treatment of NKH aims to reduce plasma concentrations of glycine and inhibit the binding of glycine to NMDA. As described earlier, glycine acts as a chemical messenger between nerve cells in the brain. It exerts its effects by binding to a receptor called NMDA (N-methyl D-aspartate).

Sodium benzoate is used to decrease plasma concentration of glycine; however, this treatment does not lower glycine levels in the CSF. Sodium benzoate increases alertness and can improve behavior in affected individuals with milder symptoms. Additionally, in patients with mild or attenuated forms, sodium benzoate diminishes lethargic episodes that are observed.

Another group of drugs used to treat NKH are NMDA receptor site antagonists. These are molecules that do not allow glycine to bind to the NMDA receptor, thus, inhibit its effects. In attenuated or mild forms, NMDA antagonists improve alertness and seizure control.

Additionally, standard anti-seizure drugs are not effective for neonates affected by NKH. However, the nature of the seizures change in older infants. Thus, some standard anti-seizure drugs may be used in older affected children to control seizures. Ketogenic diet as also shown variable effectiveness to control seizures. The ketogenic diet is a low-carb, high-fat diet used to control seizures. This diet increases the blood levels of a group of molecules known as ketones. Elevated levels of ketone bodies in the blood reduces the frequency of seizures.

Unfortunately, these treatments are usually ineffective in individuals with severe NKH. However, a vagal nerve stimulator has shown varying levels of success for control of seizures that are difficult to treat in the severe form. Vagal nerve stimulation is a procedure where a device is implanted in the body that stimulates a nerve called to vagus nerve. This procedure is used to treat seizures when other treatments have been ineffective.

 

The prognosis of NKH depends on a number of factors including the age at onset, presence or absence of brain malformations, and CSF and plasma glycine levels. However, generally the affected individuals with the neonatal form have poor outcomes and life expectancy compared to individuals affected by the infantile forms. The best outcome that has been reported in NKH is normal intelligence in affected individuals who exhibit residual glycine cleavage system enzymatic activity who obtained aggressive and early treatment. Residual enzymatic activity is seen in individuals who have a disease-causing variant in one of the associated genes; however, the variant leads to production of a protein that has enzymatic activity but lower than normal.

 

Valproate is an anti-seizure medication that is contraindicated in NKH because it increases blood and CSF glycine levels. This may lead to increased siezure frequency, lethargy, and coma.

 

Van Hove J, Coughlin C II, Scharer G. Glycine Encephalopathy. 2002 Nov 14 [Updated 2013 Jul 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1357/

Applegarth D, Toone J. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Molecular Genetics and Metabolism. 2001;74(1-2):139-46. DOI: 10.1006/mgme.2001.3224

Genetic Home Reference. Glycine encephalopathy. 2018. Available from https://ghr.nlm.nih.gov/condition/glycine-encephalopathy#synonyms

Applegarth D, Toone J. Glycine encephalopathy (nonketotic hyperglycinaemia): Review and update. Journal of Inherited Metabolic Disease. 2004;27(3):417-422. DOI: https://doi.org/10.1023/B:BOLI.0000031222.38328.59

Hennermann J. Clinical Variability in Glycine Encephalopathy. Future Neurology. 2006;1(5):621-630.

DOI: https://doi.org/10.2217/14796708.1.5.621

Ramirez N, Flynn JM, Casalduc F, Rodriguez S, Cornier AS, Carlo S. Musculoskeletal manifestations of neonatal nonketotic hyperglycinemia. J Child Orthop. 2012;6(3):199-203.

 

hello Created by dhalia
Last updated 1 Jul 2011, 09:59 AM

Posted by Northwest
1 Jul 2011, 09:59 AM

Hi Dhalia, I'm really sorry to hear about your little girl being diagnosed with NKH. We have a 15month old son who also has NKH, he was diagnosed at 8 days old and has the very severe form although he does now feed by mouth, cries when he us unhappy and hits toys that are near him. He has a few fits a day although some days he has none at all. Is your little girl on medication? There is a great support network, the NKH network and Judy Clifford will put you in touch with other families who might live near you. It's really hard because like you, we just don't know what the future holds for our son but all we can do is make him as comfortable as we can and enjoy every day we have with him. All the best and let me know if you have any questions.

Posted by dhalia
30 Jun 2011, 07:05 AM

I'm new here... My first and only child was recently diagnosed with non-ketotic hyperglycinemia. She's 7-month-old and I'm very affraid of what is going to happen. Please, I would like to know how others cope with this...

hi all Created by nkhmom1
Last updated 8 Jun 2010, 01:48 PM

Posted by Lwyde
8 Jun 2010, 01:48 PM

not sure how to use this site yet, but trying to figure it out

Posted by nkhmom1
16 Dec 2008, 02:40 AM

Hey its missy from ohio. Ryan Miller's mom. if anyone is on here let me know. hope everyone has a great holiday. Missy

Hi Created by Rachel
Last updated 21 Feb 2009, 06:01 PM

Posted by Judy
21 Feb 2009, 06:01 PM

Hi...feel free to email me at catrosenkh@yahoo.com and ask away. Also you can join our website at www.nkh-network.org to read the message board or sign up to be able to post questions or replys. ~Judy

Community External News Link
Title Date Link
Community Resources
Title Description Date Link
NKH International Family Network

We are a parental run support group where we offer information & guidance to those who have/had a child with NKH.

03/20/2017

Clinical Trials


Cords registry

CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access.

Enrolling is easy.

  1. Complete the screening form.
  2. Review the informed consent.
  3. Answer the permission and data sharing questions.

After these steps, the enrollment process is complete. All other questions are voluntary. However, these questions are important to patients and their families to create awareness as well as to researchers to study rare diseases. This is why we ask our participants to update their information annually or anytime changes to their information occur.

Researchers can contact CoRDS to determine if the registry contains participants with the rare disease they are researching. If the researcher determines there is a sufficient number of participants or data on the rare disease of interest within the registry, the researcher can apply for access. Upon approval from the CoRDS Scientific Advisory Board, CoRDS staff will reach out to participants on behalf of the researcher. It is then up to the participant to determine if they would like to join the study.

Visit sanfordresearch.org/CoRDS to enroll.

Community Leaders

 

Expert Questions

Ask a question

Community User List

Hello, <p>&nbsp;</p> <p>&nb...
I'm a mother to 7-month-old...
I am a speech/language path...
My daughter Emily was born ...
...........................
Identical twin sons, Mark &...
I have a 14 yr old son who ...
Mum to NKH Angel, Heather.
great gdson has this disease
I am the mother of a deceas...
I HAVE A NON-PROFIT ORGANIZ...
I am 19 years old. I was b...
Hello! <p>&nbsp;</p> <p>&nb...
I have 2 grandson's.Dylan w...
I'm a young mother from Rom...
I am greatly blessed with 6...
I have three kids one that ...
I have two daughters, ages ...
I have a daughter born with...
I have a child with Non-ket...

Start a Community


Don't See Your Condition On Rareshare?

Start your own! With a worldwide network of 8,000 users, you won't be the only member of your community for long.

FAQ


Have questions about rareshare?

Visit our Frequently Asked Questions page to find the answers to some of the most commonly asked questions.

Discussion Forum

hello

Created by dhalia | Last updated 1 Jul 2011, 09:59 AM

hi all

Created by nkhmom1 | Last updated 8 Jun 2010, 01:48 PM

Hi

Created by Rachel | Last updated 21 Feb 2009, 06:01 PM


Communities

Our Communities

Join Rareshare to meet other people that have been touched by rare diseases. Learn, engage, and grow with our communities.

FIND YOUR COMMUNITY
Physicians

Our Resources

Our rare disease resources include e-books and podcasts

VIEW OUR EBOOKS

LISTEN TO OUR PODCASTS

VIEW OUR GUIDES

Leaders

Our Community Leaders

Community leaders are active users that have been touched by the rare disease that they are a part of. Not only are they there to help facilitate conversations and provide new information that is relevant for the group, but they are there for you and to let you know you have a support system on Rareshare.