An Overview of Nonketotic Hyperglycinemia (NKH)

Nonketotic hyperglycinemia (NKH) is a genetic condition that can lead to serious neurological problems, coma, and death. “Hyperglycinemia” refers to abnormally high levels of a molecule, glycine. The word “nonketotic” distinguishes NKH from certain other health conditions that can cause increased glycine. The condition is also sometimes called "glycine encephalopathy," meaning a disease that damages the brain.

NKH belongs to a larger group of medical conditions called “inborn errors of metabolism.” These are genetic defects that lead to problems making certain chemical conversions in the body. NKH is a rare condition: it is diagnosed in roughly one in 60,000 newborns. However, it may be more common in specific subpopulations, like in certain areas of Israel.

Symptoms

People with NKH can have variable intensity and degree of symptoms. Researchers aren’t yet sure why, but boys tend to have less severe symptoms compared to girls, and they are more likely to survive. Most commonly, symptoms begin soon after birth. These infants show symptoms like the following:

Symptoms may worsen, leading to a total lack of responsiveness and coma. Unfortunately, death is not uncommon. When infants survive this initial period, the affected individuals almost always have additional symptoms. For example, these might include severe developmental disability or seizures that are very difficult to treat.

Less commonly, people may suffer from an atypical form of the disease. In some of these atypical cases, the disease is milder. For example, the individual might have intellectual disability, but not nearly as severely.

In the most common of the atypical forms, symptoms begin later in infancy, but in other cases, symptoms may not begin until later in childhood. These people may appear normal but then develop symptoms that affect primarily the nervous system. These might include:

For people whose symptoms begin in infancy, about 50% will have a more mild form of the disease.

Extremely rarely, infants experience something called “transient NKH." Some experts consider this a controversial diagnosis. In these cases, glycine levels are very high at birth, but for unknown reasons, they then decrease to normal or near-normal levels. These infants may experience temporary symptoms that completely go away by the age of two months.

In other cases, individuals with transient NKH go on to experience some long-term problems, like intellectual disability. Researchers aren’t sure how to explain this very uncommon form of the disease. It may be that it results from slow maturation of the enzyme that is affected in other forms of NKH.

Causes

The symptoms of NKH result from abnormally high levels of glycine, a small molecule. Glycine is a normal amino acid, one of the components used to make proteins in your body. Glycine also normally plays an important role in the nervous system, where it serves as a chemical messenger for various signals.

Normally, glycine is broken down by an enzyme before levels build up too high. When there is a problem with this enzyme (called the glycine cleavage system), NKH can result. This is caused by abnormal genetic mutations in one of the proteins used to make the enzyme. Most of the time this is due to a mutation in one of two genes—the AMT or the GLDC gene.

Because of these mutations, excess glycine builds up in the body, particularly the brain and the rest of the nervous system, which leads to the symptoms of NKH. It’s thought that people with the milder version of NKH may have more minor problems with the glycine cleavage system. This prevents glycine levels from getting as high as they do in people with the severe form of the disease.

Diagnosis

Diagnosis of NKH can be challenging. A physical exam and one's medical history play an important role in the diagnosis. In infants with symptoms like low muscle tone, seizures, and coma, healthcare providers need to consider the possibility of NKH. Healthcare providers also need to rule out the possibility of medical conditions that can cause similar symptoms. A wide variety of syndromes can cause problems like seizures in infants, including many different genetic problems.

Testing plays an important role in diagnosis. Some of the key tests check for elevated levels of glycine. This might include tests of glycine in the blood, urine, or cerebrospinal fluid. However, certain medical conditions can mimic some of the laboratory findings of NKH. These include other rare disorders of metabolism, including propionic acidemia and methylmalonic acidemia. Treatment with certain anti-epileptic drugs, like valproate, can also confuse the diagnosis, since they may also cause elevated levels of glycine.

To confirm a diagnosis of NKH, genetic tests (from a blood or tissue sample) can check for abnormalities in one of the genes known to cause NKH. Less commonly, a liver biopsy might also be needed to confirm the diagnosis.

As part of the diagnosis, it’s also important to assess how much damage has been done from NKH. For example, this might require tests like MRI of the brain or an EEG. It’s also important to have specialists perform neurological and developmental assessments.

Treatment

Infants with NKH are usually very ill and require treatment in a neonatal intensive care unit (NICU). Here they can receive high levels of intervention and care.

Unfortunately, there is no real treatment for the more common and severe forms of NKH. However, for people with less severe disease, there are some treatments that may help somewhat. These are most likely to provide some benefit if they are given early and aggressively. These include:

• Drugs to lower the levels of glycine (sodium benzoate)
• Drugs that oppose the action glycine at certain neurons (like dextromethorphan or ketamine)

It’s also important to treat seizures in NKH. These can be very difficult to address with standard medications such as phenytoin or phenobarbital. Successful treatment may require a combination of antiepileptic medications. Sometimes other interventions may be needed to help control seizures, like vagal nerve stimulators or special diets.

It’s also worth investigating the possibility of clinical trials. Ask your healthcare provider or search the government database for clinical trials to see if there are medical studies that might benefit your child.

Inheritance

NKH is an autosomal recessive genetic condition. That means a person with NKH has to receive an affected gene from both their mother and their father. People with only one affected gene do not get the condition.

Much less commonly, NKH can arise from a sporadic mutation. That just means that a child can rarely be born with NKH, even if only one of their parents carries the affected mutation.

Working with a genetic counselor is often very helpful if someone in your family was born with NKH. This professional can give you a sense of the risks in your particular situation. Prenatal testing is also available if there is a risk of NKH. In vitro fertilization may also be an option for couples who want to pre-screen embryos for the disease.

A Word From Verywell

A diagnosis of NKH is a devastating one for families. It can be overwhelming to learn that your young child has a disease for which there is very little treatment. It is tragic to lose one’s child; children that do survive will need a lifetime of support and care. Networking with other families can be a powerful way to get information and a sense of connection. Know that your healthcare team is here to support you in whatever way is possible. Don’t hesitate to reach out to your support system whenever you need to.