NKH stands for nonketotic hyperglycinemia, a rare inherited metabolic disorder in which the body cannot properly break down glycine, one of the simplest amino acids. The result is a dangerous buildup of glycine in the blood, spinal fluid, and brain, causing severe neurological problems that typically appear within the first days of life. NKH is also called glycine encephalopathy.
What Happens in the Body
Glycine is a normal part of your body’s chemistry. It acts as a building block for proteins and also functions as a signaling molecule in the brain and spinal cord. Normally, a set of four proteins working together (called the glycine cleavage system) breaks glycine down when levels get too high. In NKH, this system doesn’t work. Glycine accumulates in every tissue, but the damage concentrates in the brain.
The problem is a loss-of-function defect in the genes that code for parts of this enzyme system. About 80% of cases involve mutations in the GLDC gene, which produces the protein responsible for the first step in glycine breakdown. The remaining 20% involve the AMT gene, which handles the second step. Both parents must carry a copy of the faulty gene for a child to be affected, following an autosomal recessive inheritance pattern. That means carriers, people with only one mutated copy, show no symptoms.
Why Excess Glycine Damages the Brain
Glycine plays two very different roles in the nervous system. In the spinal cord and brainstem, it acts as an inhibitory signal, calming nerve activity. When glycine floods these areas, it suppresses basic functions like breathing and muscle tone. This is why newborns with NKH often have episodes of stopped breathing (apnea) and extremely low muscle tone.
In the upper brain, glycine does the opposite. It helps activate a type of receptor called the NMDA receptor, which is involved in learning, development, and nerve signaling. Too much glycine overstimulates these receptors, which can damage developing brain tissue and trigger seizures. This dual mechanism, too much inhibition in the brainstem and too much excitation in the brain, explains the wide range of neurological symptoms NKH produces.
Symptoms of the Classic Neonatal Form
The neonatal form is the most common presentation. Symptoms appear within the first 6 hours to 8 days of life and progress rapidly. A newborn with classic NKH typically shows poor feeding, an inability to suck, extreme sleepiness, and profound floppiness. Without intervention, this can escalate into deep coma, breathing failure, and death.
Seizures, particularly myoclonic jerks (sudden, brief muscle twitches), are common. Persistent hiccups are a notable early sign, and some mothers report frequent hiccup-like movements even before birth, caused by glycine accumulating in the womb. This combination of persistent hiccups, seizures, reduced reflexes, floppiness, and breathing difficulties in a newborn is a strong signal for clinicians to investigate NKH.
Atypical and Later-Onset Forms
Not all NKH presents in the newborn period. Atypical forms fall into three categories: a neonatal type that looks like the classic form initially but has a significantly better outcome, an infantile type that appears later in the first year, and a late-onset type that may not surface until childhood or even adulthood. The clinical picture in these later forms is much more varied. Intellectual disability and behavioral problems are the most consistent features, but the severity ranges widely. Late-onset cases can be particularly hard to diagnose because the symptoms are less dramatic and overlap with many other conditions.
How NKH Is Diagnosed
The key diagnostic test measures glycine levels in both the blood and the cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord. Both samples need to be collected at the same time. In NKH, CSF glycine is typically 15 to 30 times higher than normal. The critical number is the ratio of CSF glycine to blood glycine: a ratio above 0.08 is considered diagnostic. In classic severe cases, the ratio often exceeds 0.2, while atypical or milder cases tend to cluster around 0.09.
This ratio also carries prognostic information. Higher CSF glycine levels (above 230 micromoles per liter) predict a severe outcome. A ratio at or below 0.08 points toward a milder, attenuated form with a better developmental trajectory. Genetic testing of the GLDC and AMT genes confirms the diagnosis and identifies the specific mutations involved, which can be useful for family planning.
Treatment and Management
There is no cure for NKH, and treatment focuses on reducing glycine levels and protecting the brain from overstimulation. The two main approaches work on different parts of the problem.
Lowering Glycine Levels
Sodium benzoate is the primary drug used to pull glycine out of the bloodstream. It works by binding to glycine and creating a compound the kidneys can excrete. The goal is to bring blood glycine levels down to the normal range. Higher doses reduce seizures and improve alertness, but there is a ceiling: pushing the dose too high leads to toxic benzoate levels. The amount of benzoate each patient needs varies substantially depending on how much residual enzyme activity they have and how much glycine they take in through food.
Researchers have found that patients with severe NKH need roughly two to five times more benzoate per kilogram of body weight to normalize glycine levels compared to patients with milder forms. This difference in drug requirement, called the glycine index, itself correlates with outcomes: children who need the highest doses tend to have the poorest developmental results.
Blocking Brain Overstimulation
Because excess glycine overstimulates NMDA receptors in the brain, medications that block these receptors are used alongside sodium benzoate. Dextromethorphan (a compound also found in cough suppressants, but used here at much higher doses) is the most common choice. It can reduce seizures, normalize brain wave patterns, improve muscle tone, and help with breathing difficulties. Ketamine is an alternative that may provide better seizure control in some patients, though it carries side effects like excessive sleepiness, agitation, and involuntary movements.
Timing matters enormously. Studies comparing siblings with NKH have shown that children who start both sodium benzoate and an NMDA-blocking medication immediately after diagnosis, and continue through the early years, achieve the best developmental outcomes. This is especially true for children with the attenuated form, where early and sustained treatment can make a meaningful difference in reaching developmental milestones. In severe classic NKH, these medications improve comfort and reduce seizures but generally cannot prevent the underlying brain damage that has often already occurred before or shortly after birth.
Prognosis by Severity
The outlook for NKH depends heavily on which form a child has. Classic severe NKH carries a poor prognosis. Many affected infants do not survive the newborn period without intensive medical support, and those who do typically face profound intellectual disability, ongoing seizures, and limited motor development. For families facing this diagnosis, treatment decisions often center on quality of life and comfort.
Children with attenuated NKH have a wider range of outcomes. Some achieve meaningful developmental milestones, particularly when treatment begins early. Intellectual disability is still common but can range from mild to moderate. Behavioral challenges are frequent in both the infantile and late-onset forms. The CSF glycine level and CSF-to-plasma ratio at diagnosis, combined with genetic testing, give families and clinicians the best available picture of what to expect, though individual variation remains significant.