Nonketotic Hyperglycinemia

What is nonketotic hyperglycinemia?

Nonketotic hyperglycinemia (often shortened to NKH, and also called glycine encephalopathy) is a rare inherited metabolic disorder. It affects the way the body breaks down glycine, one of the amino acids (the building blocks of protein). In people with nonketotic hyperglycinemia, an enzyme system in the liver and brain called the glycine cleavage system does not work properly. As a result, glycine builds up to very high levels in the blood, the urine, and especially in the fluid that surrounds the brain and spinal cord (cerebrospinal fluid).

Glycine is not only a building block of protein. It also acts as a chemical messenger (neurotransmitter) in the nervous system. In the brainstem and spinal cord it calms nerve activity, while in higher parts of the brain it helps to excite certain nerve receptors. When glycine levels are far too high, this delicate balance is disturbed, which is why the condition mainly harms the brain and nervous system.

The word “nonketotic” is used to separate this disorder from other conditions in which glycine is also raised but the blood becomes acidic with substances called ketones. In nonketotic hyperglycinemia, ketones are not raised, and other organic acids in the urine are usually normal.

Nonketotic hyperglycinemia most often becomes apparent in newborn babies within the first days of life, although milder forms can appear later in infancy or childhood. It is a genetic condition that is present from birth and affects both boys and girls. It is very rare, and many general doctors will never see a case, so care is usually coordinated by specialists in metabolic disease and medical genetics.

Symptoms of nonketotic hyperglycinemia

Nonketotic hyperglycinemia symptoms depend on the form of the disease and on how little enzyme activity remains. Doctors generally describe two main forms: a severe (classic) form that starts in the newborn period, and a milder, or attenuated, form that starts later and varies widely between people.

Common features that may be seen include:

• Extreme sleepiness or unresponsiveness (lethargy) in a newborn
• Poor feeding and weak sucking
• Floppy muscle tone (hypotonia)
• Pauses in breathing (apnea) that may require breathing support
• Persistent hiccups, sometimes noticed by the mother during pregnancy
• Sudden jerking movements (myoclonic jerks) and seizures
• Developmental delay and intellectual disability
• Stiff or tight muscles (spasticity) developing over time
• Unusual movements such as writhing or restlessness (chorea) in milder forms
• Behavioral difficulties or hyperactivity in older children with the attenuated form

Severe (classic neonatal) form. Babies with this form are usually born looking well but become progressively sleepy and floppy within hours to a few days. They feed poorly, have weak breathing, and may develop frequent hiccups and jerky movements. Many stop breathing effectively and need a ventilator (a breathing machine) in the newborn intensive care unit. Seizures are common and can be difficult to control. In many cases, breathing improves during the first weeks of life and the baby can come off the ventilator, but the underlying brain effects remain. Children who survive the newborn period typically have profound developmental delay, ongoing seizures, and increasing muscle stiffness.

Attenuated (milder) form. Some children have a partly working glycine cleavage system. Their symptoms may begin in later infancy or childhood and are usually less severe. Features can include developmental delay of varying degree, low muscle tone, seizures that are often more treatable, abnormal movements, and behavioral or attention problems. Some children with the attenuated form learn to walk and communicate, while others have greater difficulties. Because this form is so variable, it is not possible to predict outcomes from symptoms alone.

A very rare transient form has also been reported, in which glycine levels are high in a newborn but later return toward normal. Because it can look identical to the classic form at first, doctors are cautious about using this label until follow-up testing confirms it.

Causes and risk factors

Nonketotic hyperglycinemia causes are genetic. The condition results from changes (variants) in genes that provide instructions for the parts of the glycine cleavage system. The genes most often involved are GLDC and AMT; a third gene, GCSH, is involved only rarely. When these genes do not work correctly, the enzyme system cannot break glycine down, so glycine accumulates.

The condition is inherited in an autosomal recessive pattern. This means a child is affected only when both copies of the gene, one from each parent, carry a harmful change. The parents each carry one changed copy and one normal copy and are usually healthy, without any symptoms. Such parents are called carriers.

Risk factors relate to family history rather than lifestyle:

• Both parents being carriers of a harmful variant in the same gene. In each pregnancy, such parents have a 1 in 4 chance of having an affected child.
• A previous child with nonketotic hyperglycinemia in the family.
• Parents who are related by blood (consanguinity), which makes it more likely that both carry the same rare variant.

It is important to understand that nothing a parent did or did not do during pregnancy causes this condition. Diet, infections, medications, and stress during pregnancy do not cause nonketotic hyperglycinemia. It is entirely determined by the genes the child inherits.

Diagnosis of nonketotic hyperglycinemia

Because the early signs resemble many other serious newborn illnesses, such as infection, lack of oxygen at birth, or other metabolic disorders, nonketotic hyperglycinemia diagnosis requires specific laboratory testing. Doctors usually suspect the condition in a newborn with unexplained sleepiness, floppiness, breathing pauses, hiccups, and seizures, particularly when routine tests for infection and other causes are normal.

Tests that are commonly used include:

• Plasma amino acid analysis. A blood test that measures amino acid levels and shows a raised glycine level.
• Cerebrospinal fluid (CSF) glycine. A sample of spinal fluid obtained by lumbar puncture (a spinal tap). In nonketotic hyperglycinemia, glycine in the spinal fluid is very high, and the ratio of CSF glycine to blood glycine is abnormally elevated. This ratio is a key finding, so doctors try to collect the blood and spinal fluid samples at about the same time.
• Urine organic acids and blood tests for ketones and acid-base balance. These help rule out “ketotic” hyperglycinemias, such as propionic acidemia and methylmalonic acidemia, in which glycine is also raised but the body becomes acidic.
• Genetic testing. Analysis of the GLDC, AMT, and GCSH genes confirms the diagnosis in most cases and allows carrier testing for parents and, if wished, testing in future pregnancies.
• Electroencephalogram (EEG). A recording of brain electrical activity. In severe newborn cases it often shows a characteristic pattern called burst suppression, with bursts of activity separated by flat periods.
• Brain MRI (magnetic resonance imaging). Imaging may show underdevelopment of the corpus callosum (the bridge of nerve fibers connecting the two halves of the brain) or changes in the developing white matter. A special MRI technique called magnetic resonance spectroscopy can sometimes detect a glycine signal in the brain.

In the past, the diagnosis was sometimes confirmed by measuring enzyme activity in a small piece of liver tissue. Today this is rarely needed because genetic testing is usually able to confirm the condition. Standard newborn screening programs do not reliably detect nonketotic hyperglycinemia, so a normal newborn screen does not rule it out.

Once the diagnosis is confirmed, families are usually referred for genetic counseling, where a specialist explains the inheritance pattern, the implications for other family members, and the options available for future pregnancies. In the Acibadem network this is coordinated through the Medical Genetics Department together with pediatric metabolic and neurology teams.

Treatment options for nonketotic hyperglycinemia

At present there is no cure for nonketotic hyperglycinemia, and no treatment can repair the faulty enzyme system. Nonketotic hyperglycinemia treatment therefore focuses on lowering glycine levels, reducing the effects of glycine on the brain, controlling seizures, supporting breathing and nutrition, and helping the child reach the best possible level of comfort and function. Treatment is highly individualized and is usually led by a metabolic specialist working with a pediatric neurologist.

Supportive care in the newborn period. Babies with the severe form often need admission to an intensive care unit. This may include a ventilator for breathing pauses, feeding through a tube, and treatment of seizures. Doctors and families also discuss the expected outlook together, since the severity of the condition varies and decisions about intensive treatment are deeply personal.

Sodium benzoate. This medication binds to glycine in the body to form a compound that is removed in the urine. It can bring blood glycine levels down toward the normal range, which may help reduce seizures and improve alertness, especially in the milder form. Its effect on spinal fluid glycine is smaller. Blood levels of the drug and of glycine need regular monitoring because too high a dose can be toxic, and the medication can lower levels of a nutrient called carnitine, which may need to be replaced.

Medications that block glycine’s excitatory action. Dextromethorphan and, in some settings, ketamine act on brain receptors (NMDA receptors) where glycine has a stimulating effect. These drugs are sometimes used, usually together with sodium benzoate, in an attempt to reduce seizures and improve development. The response varies widely, and the benefit tends to be greater in children with the attenuated form than in those with the classic severe form.

Anti-seizure medications. Seizures are a major problem in this condition and often require one or more anti-seizure drugs. Doctors generally avoid valproate (valproic acid), because it can further inhibit the glycine cleavage system and raise glycine levels. Some centers have tried a ketogenic diet (a carefully supervised high-fat, low-carbohydrate diet) for difficult seizures, but evidence is limited and it is not standard treatment.

Nutrition. Many affected children have difficulty sucking and swallowing. A feeding tube, sometimes a long-term tube placed into the stomach (gastrostomy), may be recommended to ensure safe and adequate nutrition. Restricting glycine in the diet has not been shown to be helpful on its own, because the body makes glycine itself.

Rehabilitation and long-term care. Physical therapy, occupational therapy, and speech and feeding therapy can help with muscle tone, positioning, comfort, and communication. Children with stiffness may need medications for spasticity, braces, or in some cases orthopedic procedures for hip problems or curvature of the spine (scoliosis). Regular follow-up also covers vision, hearing, growth, and breathing during sleep.

Palliative and family support. For children with the severe form, palliative care teams can help with symptom control and quality of life alongside active treatment. Support for parents and siblings is an important part of care throughout.

Living with nonketotic hyperglycinemia and outlook

The outlook for nonketotic hyperglycinemia depends mainly on the form of the disease. In the classic severe newborn form, the condition is life-limiting. Some babies do not survive the newborn period, and those who do usually have profound developmental disability, ongoing seizures that are hard to control, and progressive muscle stiffness. They typically need full-time care throughout their lives.

In the attenuated form, the outcome is much more variable. Some children have moderate developmental delay, achieve mobility, and communicate to some degree, while others are more severely affected. Early treatment with sodium benzoate and NMDA-blocking medications appears to help some children in this group, although it does not normalize development. Because the range is so wide, doctors are cautious about predicting how any individual child will do.

Families living with this condition often manage a complex daily routine that includes medications, feeding, therapy sessions, and frequent medical appointments. Coordinated care with a single team that knows the child well can make this easier. Genetic counseling gives parents accurate information about the risk in future pregnancies and about options such as prenatal testing or testing of embryos, if they wish to consider them.

Research into new treatments for nonketotic hyperglycinemia is ongoing, but no therapy currently changes the underlying genetic cause. Families may wish to ask their care team whether any clinical studies are open to them.

Frequently asked questions

What are the first nonketotic hyperglycinemia symptoms in a newborn?

In the classic form, the earliest signs are usually unusual sleepiness, weak feeding, and floppy muscle tone appearing within the first hours to days after birth. Persistent hiccups, jerky movements, and pauses in breathing often follow. These signs are not specific to this condition and can have many other causes, so doctors run tests to find the reason rather than relying on symptoms alone.

What causes nonketotic hyperglycinemia?

Nonketotic hyperglycinemia causes are entirely genetic. A child inherits a changed copy of the GLDC, AMT, or, rarely, GCSH gene from each parent. These genes control the enzyme system that breaks down glycine. The parents are usually healthy carriers and are typically unaware they carry the change until an affected child is born. Nothing during pregnancy causes or prevents the condition.

How is nonketotic hyperglycinemia diagnosis confirmed?

Diagnosis is based on finding very high glycine in the blood and spinal fluid, with an abnormally high ratio between the two, together with normal tests for ketones and organic acids that rule out related disorders. Genetic testing of the relevant genes is then used to confirm the diagnosis and to guide family counseling. An EEG and brain MRI provide supporting information.

Is there a cure or effective nonketotic hyperglycinemia treatment?

There is no cure. Treatment aims to lower glycine levels with sodium benzoate, to reduce glycine’s effects on the brain with medications such as dextromethorphan, to control seizures, and to support breathing, feeding, and development. These measures may improve alertness and seizure control in some children, particularly those with milder disease, but they do not restore normal development.

Does nonketotic hyperglycinemia show up on newborn screening?

Usually not. Routine newborn screening panels are designed for other metabolic disorders and glycine measured on a heel-prick sample is not a reliable marker for this condition. A normal newborn screen therefore does not exclude nonketotic hyperglycinemia, and specific testing is needed when the diagnosis is suspected.

Can nonketotic hyperglycinemia be detected before birth?

Yes, in families where the genetic changes have already been identified in an affected child or in both parents. Prenatal genetic testing can be performed on a sample taken during pregnancy, and in some cases testing of embryos before implantation is an option. A genetic counselor can explain what is available and the limitations of each approach.

Why is valproate avoided in children with nonketotic hyperglycinemia?

Valproate, a commonly used anti-seizure medication, can further block the glycine cleavage system and raise glycine levels, which may worsen symptoms. For this reason doctors usually choose other anti-seizure medications. Parents should make sure that any doctor treating their child is aware of the diagnosis before new medications are prescribed.

When to see a doctor

Nonketotic hyperglycinemia is a medical emergency in its early stages, and children with a confirmed diagnosis can become unwell quickly. Seek urgent medical care if a newborn or a child with this condition shows any of the following:

• Pauses in breathing, blue or gray color of the lips or skin, or very slow breathing
• A newborn who is unusually sleepy, difficult to wake, or too weak to feed
• Repeated jerking movements or a seizure, especially one lasting more than a few minutes or occurring in clusters
• Persistent hiccups together with floppiness or poor feeding in a newborn
• Vomiting, refusal to feed, or signs of dehydration such as very few wet diapers
• Fever or another illness in a child known to have the condition, since infections can worsen seizures and breathing
• A sudden change in alertness, muscle tone, or movement pattern compared with the child’s usual state

Families of a child with a known diagnosis should also arrange a routine review if seizures become more frequent, feeding becomes more difficult, muscle stiffness increases, or there are concerns about growth or sleep. Parents who have had a child with nonketotic hyperglycinemia and are planning another pregnancy may wish to ask their doctor about genetic counseling before conception.