Nonketotic Hyperglycinemia

What is NKH?

Nonketotic hyperglycinemia (NKH) is a rare genetic disorder that prevents your baby’s body from processing a molecule called glycine.

Glycine is an amino acid, the building block of protein. When your baby’s body can’t process glycine properly, it builds up in their organs and tissues, especially in their brain. This leads to abnormally high levels of glycine in their body (hyperglycinemia) which can lead to severe neurological issues, coma and death. “Nonketotic” differentiates the condition from other diseases that can cause high levels of glycine in your body.

NKH is an inborn error of metabolism, which are birth defects (congenital conditions) that lead to problems producing certain chemical conversions in your baby’s body. Another name for NKH is glycine encephalopathy.

Types of NKH

Researchers classify NKH into different forms: classical and variant. Two types of genetic mutations can cause NKH. The classical and variant forms of NKH refer to which gene has a mutation.

Experts further divide the classical form into a severe disorder or a mild form (attenuated form). They’re distinguished by the seriousness of the symptoms of the disease. Severe NKH is the more common form.

How common is this condition?

NKH is rare. It affects about 1 in every 76,000 babies worldwide.

What are the symptoms of NKH (nonketotic hyperglycinemia)?

Severe and attenuated forms of NKH typically start shortly after birth, but sometimes, NKH symptoms start in the first few months of life. Infants with severe NKH may have extreme sleepiness (lethargy) that gets worse over time and can lead to coma. Babies may also experience weak muscle tone (hypotonia) and life-threatening breathing problems at the beginning of life.

If babies survive these first few signs and symptoms, they’ll typically go on to develop:

• Feeding issues.
• Pauses in breathing (apnea).
• Extreme intellectual disability.
• Abnormal muscle stiffness (spasticity).
• Difficult-to-control seizures.

Most children don’t achieve typical developmental milestones, like grabbing items, sitting up or drinking from a bottle. If they do achieve these milestones, they may lose these abilities (regress) over time.

The symptoms of the attenuated form of NKH are milder than the severe form, but they’re similar. Children with attenuated NKH usually reach developmental milestones, but their skills and abilities will vary widely. Development may be delayed, but many children eventually learn to walk and can interact with others. Some children develop seizures, but they’re typically mild and can be treated. Other mild NKH symptoms may include involuntary jerking movements (chorea), spasticity and hyperactivity.

What causes NKH in babies?

Gene changes (mutations) cause NKH. Specifically, mutations in the GLDC gene cause approximately 80% of cases. And changes in the AMT gene cause the rest.

The GLDC and AMT genes tell your body how to make certain enzymes that work together as a group. This group — called the glycine cleavage system — breaks glycine down into smaller pieces when you don’t need it anymore. Too much glycine disrupts brain function.

Mutations in either of these genes make it harder for your body to break down glycine. Some mutations lessen the activity of the glycine cleavage system, and other mutations eliminate it completely. When this system isn’t working properly, extra glycine builds up in your baby’s organs and tissues, especially in their brain. Scientists don’t know why these abnormalities contribute to the characteristics of NKH.

You can inherit NKH in an autosomal recessive pattern. That means both copies of the gene in each cell have mutations. Usually, the biological parents of someone with NKH each carry one copy of the mutated gene, but they don’t develop symptoms of the condition.

How is NKH diagnosed?

To make an NKH diagnosis, your baby’s healthcare provider will perform a physical exam and evaluate their symptoms. They’ll also test their cerebral spinal fluid (CSF) and plasma glycine levels. When the enzyme activity is deficient, it causes elevated glycine levels in CSF and plasma. It also causes an elevated CSF to plasma glycine ratio.

A brain MRI can also be helpful because there’s a specific pattern of brain changes seen in babies with NKH.

Genetic testing can check for mutations in one of the two genes known to cause NKH, too. Less commonly, your child’s provider might perform a liver biopsy to confirm the diagnosis.

How is nonketotic hyperglycinemia (NKH) treated?

Babies with nonketotic hyperglycinemia are typically very sick and will require NKH treatment in a neonatal intensive care unit (NICU). Your baby will receive high levels of care and intervention in the NICU.

Unfortunately, there isn’t a treatment available for the severe form of NKH. But for babies with the mild form, there are some treatments that may be helpful. These are most likely to prove effective if given early and aggressively. These treatments include the following, alone or in combination:

• Medication to lower your baby’s levels of glycine (sodium benzoate).
• Medication that opposes the action of glycine at particular neurons (like ketamine or dextromethorphan).

The management of seizures is also important. Seizures may be hard to treat with standard medications. Successful treatment may require a combination of medications, avoiding a particular one called valproic acid. A ketogenic diet can help control seizures.

Treatment for other NKH symptoms may include:

• Mechanical ventilation.
• Gastrostomy tube.
• Physical therapy.
• Early interventions and additional support.

You may also wish to explore the possibility of participating in a clinical trial. Ask your healthcare provider about any options that may be available.

Can this be prevented?

NKH is a genetic condition that can’t be prevented. If you’re concerned about passing on the condition to your child, you may wish to speak to a genetic counselor before planning for pregnancy

What is the life expectancy of someone with NKH?

The prognosis or life expectancy of someone with NKH disease is difficult to say because there are different genetic mutations and the severity of the disease varies widely. However, The Foundation for Nonketotic Hyperglycinemia estimates that 80% of babies with the disease won’t survive the neonatal phase. If they do survive the neonatal phase, most children with severe NKH won’t survive past their 5th birthday. Your baby’s healthcare team will be able to give you a better idea of what to expect. Lean on them for expertise and support.

When should my baby see their healthcare provider?

If your newborn baby is showing signs of extreme tiredness (lethargy) and isn’t interested in feeding, you should see their pediatrician right away. Their pediatrician may tell you to head to the ER for immediate treatment. No matter what’s causing these symptoms, it’s important to get them checked out right away.

What questions should I ask my baby’s healthcare provider?

If your baby has NKH, you may have the following questions:

• What caused NKH?
• What form of NKH does my baby have?
• What treatment options do you recommend?
• Are there any tests that can help predict the severity of this illness?
• Developmentally, how much will my baby be able to achieve (walking, talking, intellect)?
• Will my baby have to be on medications for their whole life?
• Will my future children have NKH?
• Can you recommend a support group?