Nonketotic Hyperglycinemia

Updated July 2, 2019

This article was scientifically reviewed by YourDNA

We take the information we share seriously. Review our Editorial Policy Here.

A list of references is also included at the bottom of this article.

Many neurological problems can stem from nonketotic hyperglycinemia. This rare genetic disorder, sometimes also known as Glycine Encephalopathy, causes an excess accumulation of glycine within the fluids and tissues of the body.

What's in this Guide?

Disclaimer: Before You Read

It is important to know that your genes are not your destiny. There are various environmental and genetic factors working together to shape you. No matter your genetic makeup, maintain ideal blood pressure and glucose levels, avoid harmful alcohol intake, exercise regularly, get regular sleep. And for goodness sake, don't smoke.

Genetics is a quickly changing topic.

The disease may be minor or severe depending on when it develops and how your body handles the excess glycine buildup. Here at, we want you to have the information you need to make decisions for yourself or your family if you are facing a diagnosis of this disorder.

What Is Nonketotic Hyperglycinemia?

Nonketotic hyperglycinemia (NKH) is essentially a defect within the enzyme system 1. It is a disorder passed down by genetics. 

Normal glycine levels are only achieved when the body breaks down amino acids and processes them as intended. With this disorder, the body cannot properly break down or process certain proteins or amino acids.

Because of this, glycine levels rise to abnormal levels and cause harm to the body. 

What Is Glycine, and What Is it Used For?

Glycine is one of the simplest amino acids found in the body. It is naturally produced by the body but can also be provided by certain foods and in supplements. It is used in the creation process of protein which is needed for maintaining the tissues and making hormones and enzymes.

Too little and too much glycine can have negative impacts on the body. In the case of NKH, it is too much of it that is the problem. 

The Glycine Cleavage System

The glycine cleavage system 2, also referred to as the glycine decarboxylase complex, is comprised of four proteins. H, L, P, and T proteins are all included. The H-protein interacts with the other three and is the final shuttle getting the electrons to their necessary places. 

Mutations within this system can cause problems such as glycine encephalopathy. This system is responsible for the production of carbon dioxide, ammonia, methylenetetrahydrofolate and more.

Too much glycine in the body can lead to too much of these as well, causing more problems. 

Glycine Toxicity

Having too much glycine in the body, which happens when you have NKH, can lead to glycine toxicity. Problems with the central nervous system may develop, including blindness and brain damage.

It can also lead to ammonia toxicity since ammonia is developed during glycine metabolism. This too can lead to brain disease or damage. 

Signs and Symptoms of Nonketotic Hyperglycinemia

Symptoms of NKH vary from one person to the next. Newborns who have the disease may show different signs than adults with an onset of the disorder later in life. 

It also appears that boys with the disease tend to have less severe symptoms than girls who have it. They are also more likely to survive.

It’s important to take note of any unusual symptoms you ever experience so you can look out for signs of a developing disorder or illness such as this one. 

Symptoms include:

  • Long periods of sleep
  • Difficulty breathing
  • Difficulty feeding
  • Hiccups
  • Unusual jerky movements
  • Weak muscle tone
  • Wandering eye movements
  • Developmental delay 

Weak muscle tone is especially important to consider for infants. This may mean the child will not have enough strength to sit up or crawl, let alone walk. Difficulty breathing could lead to sleep apnea and breathing machines required.

Difficulty feeding may mean the child will never be able to feed himself and may even need a feeding tube at some point. None of these symptoms indicate a minor problem, as each one can lead to additional repercussions. 

Some people only exhibit NKH disease symptoms during times of high stress or even during illness. This mild-episodic form of NKH is much less severe and not debilitating like an earlier onset form typically is.

Some of the issues experienced may still cause delays and struggles though.

Severe nonketotic hyperglycinemia can cause worsening symptoms 3, such as seizures, behavior problems, a lack of responsiveness, and coma. Additional symptoms in those who have the atypical form of the disease include:

  • Attention-hyperactivity disorder
  • Scoliosis
  • Gastroesophageal reflux 
  • Nervous system problems
  • Abnormal muscle movements 
  • Swallowing dysfunction
  • Intellectual disability

Causes of Nonketotic Hyperglycinemia

An inherited condition like nonketotic hyperglycinemia means the disorder is passed down from a parent 4. Inheritance for this particular disorder is autosomal recessive. 

This means both parents must pass down a copy of the mutated gene in order for the child to get the mutation. It makes it much less likely to get, though it is still possible. 

Nonketotic hyperglycinemia is essentially caused by an excess of glycine. Because of the inherited mutated gene, the person’s body does not understand how to break down the glycine as intended and use it accordingly.

Instead, it builds up in places it shouldn’t and wreaks havoc on the body’s central nervous system and brain.

Diagnosis of Nonketotic Hyperglycinemia

A proper diagnosis is needed to verify the presence of nonketotic hyperglycinemia. A glycine test is one of the first steps to take.

The test looks at levels of glycine in the body to determine if they are higher than average and unusual or within normal limits. 

A gene panel that takes a look at the person’s DNA can help to determine if the markers are present. If symptoms have been exhibited already, an MRI and other tests, such as an EEG, will help examine the damage done to the brain and other areas of the body and determine the next steps.

Prenatal Diagnosis

An expectant mother who is a known carrier of the mutation should have a prenatal test conducted. It is possible to get a prenatal diagnosis this way, indicating that the child has the disorder so it is known before he or she is even born.

A chorionic villus sampling takes a tiny tissue sample to get the results. A glycine cleavage enzyme activity report is also conducted. 

Postnatal Diagnosis

One in every 55,000 newborns gets affected by NKH within Finland alone 5. This may be less severe than other diseases, but it is still one to watch out for.

Most babies who have the disorder will show signs within one week. The initial newborn screening may show elevated results. This will lead to further testing after the early signs are detected. 

Some of the early signs include long periods of sleep, wandering eye movements, jerky movements, difficulty feeding, and weak muscle tone. These signs may be difficult to detect in newborns who already have unusual movements and may have trouble feeding for other reasons. 

A follow-up test includes checking the infant’s blood, urine, and spinal fluid. A result showing high levels of glycine would be a major indicator of nonketotic hyperglycinemia.

Genetic testing may also be required for a complete diagnosis of the disorder. 

Some babies may appear normal for the first few months of life. No signs will be shown, or perhaps only minor ones that are difficult to distinguish from other typical newborn movements and struggles.

However, infants with the disorder will typically start exhibiting a worsening condition by six months of age. Parents may realize intellectual disabilities and seizures could also start. 

Differential Diagnosis of Nonketotic Hyperglycinemia

Because many different metabolic genetic disorders exist that cause the same symptoms, a differential diagnosis is often needed. This process involves differentiating between two or more disorders or diseases that may exhibit similar symptoms and pinpointing the precise one the individual has. This ensures the right course of treatment can be applied.

Genetic Tests for Nonketotic Hyperglycinemia, Are They Available?

It is possible to get a genetic test done to determine if you are a carrier of the gene that causes nonketotic hyperglycinemia. 

It is advised to speak with a genetic counselor who understands the process of testing and knows what to look for better than a general physician. If you speak with your doctor, however, he should be able to point you in the right direction of a local genetic counselor who can help.

Treatment Options for Nonketotic Hyperglycinemia 

There is no cure for nonketotic hyperglycinemia. Instead, there are only some treatment options to help some of the issues that develop because of the disorder. These options work to decrease symptoms and enhance the quality of life. 

Medications may be prescribed to reduce the frequency of seizures in those who experience them. This is the most common in infants, but older children and adults may require this as well. Diazepam is a commonly prescribed option. 

Children and adults with the disorder can also try the nonketotic hyperglycinemia diet. It may make it easier to eat and reduce some of the symptoms experienced due to the disorder and the difficulty in feeding.

A diet low in protein is best since protein only provides more glycine. Choline is said to be helpful for combating this.

Foods high in choline include fish, meat, and eggs. Taking an omega-3 fatty acid supplement can also be beneficial. 

Following a ketogenic diet may be the most helpful when it comes to nutrition battling NKH symptoms. Seafood options are ideal, as well as meat, eggs, coconut oil, cottage cheese, plain greek yogurt, cheese, and avocados.

Just be sure to watch the protein intake, which is high with these foods. Choosing low carb vegetables more often is key. Tomatoes, eggplant, broccoli, cauliflower, leafy greens, cucumbers, and bell peppers should be on the menu. 

Investigational therapies are also available for treatment. Prescriptions for dextromethorphan or sodium benzoate may be given to help reduce symptoms by binding the glycine so it does not continue to build up and create further problems.

Other options, such as quantum reflex integration with low-level light laser therapy, are possible. It may help to improve memory, lessen muscle spasticity, stimulate cell repair and growth, and more. 

Additional research and testing are underway for other methods that may help. Research using mice is being conducted. Mice with an NKH genetic alteration are ideal for collecting samples and running tests.

It’s important to take a look at the beginning stages of progression to understand which cells get affected in the process. 

Both metabolic and molecular changes can be seen this way. Further analysis can look into which chemicals within the brain are being altered.

All of this research can help to see what aspects need manipulation with medication and can ensure the right medications are created in the future.

The Prognosis of Nonketotic Hyperglycinemia (NKH) 

The prognosis is better for those with an onset of the disorder later in life than for those who are born exhibiting symptoms. The answer to the question, “is NKH fatal?” differs between infants and adults. 

Many infants with nonketotic hyperglycinemia do not make it past that first week of life. Even with treatment, there is a poor outcome for babies at this stage 6.

Others who start having seizures by six months of age can have a shortened life expectancy due to the severity of the seizure activity. People with more minor forms of the genetic condition can continue to live a full life. 

The NKH International Family Network is striving to provide awareness of the disorder. Hope for NKH is possible thanks to them. There are foundations within the U.S. and other locations looking for funds to continue their research into this disease that will continue to find more treatments and hopefully one day, a cure.

Can NKH Outcomes Be Predicted?

It is possible to predict the outcomes of NKH to an extent. Through genetic testing, in particular, people are able to tell whether or not they carry the gene for this disorder. If they do and so does their partner, then there’s a likelihood that their child will have it or at least also have the same gene to pass on. 

In those who already have the disorder, it is possible to look at symptoms as well as brain scans to determine the outcome. Those with minimal symptoms and near-normal brain activity are likely to survive compared to those with poor brain scans that show severe seizure activity and numerous symptoms.

Working closely with your doctor is still recommended in either case.

Nonketotic hyperglycinemia needs much more research and funding to help find better treatment options. This is especially true for infantile cases that unfortunately result in death much of the time.

More research and awareness of the disorder will help to ensure future generations are not as greatly impacted.

Powered by Froala Editor

Referenced Sources

  1. Nonketotic Hyperglycinemia.
    Allison Kress, Editorial Intern from the University of Notre Dame, Leah Rhodes, MS, Curtis Coughlin II, MSc, MBe, and Johan L. Van Hove, MD, PhD, Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine. Retrieved 2019.
  2. Enzyme: glycine cleavage system. Retrieved Online June 2019.
  3. Glycine encephalopathy.
    U.S. National Library of Medicine. Genetics Home Reference. June 2019.
  4. Nonketotic Hyperglycinemia.
    Johan LK Van Hove, MD, PhD, Curtis Coughlin, II, MS, MBe, Michael Swanson, PhD, and Julia B Hennermann, MD, PhD, Nov. 14 2002.
  5. Nonketotic Hyperglycinemia.
    Baby's First Test. Retrieved Online 2019.
  6. Poor outcome for neonatal-type nonketotic hyperglycemia treated with high-dose sodium benzoate and dextromethorphan.
    J Child Neurol Department of Medical Genetics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei. 2004 Jan 19.