NKH, or nonketotic hyperglycinemia, is a rare genetic condition in which a baby’s body cannot break down glycine, an amino acid that builds up to toxic levels in the brain and spinal cord. It is one of the rarer inborn errors of metabolism, and symptoms typically appear within the first few days of life. Because glycine plays a key role in how nerve cells communicate, the buildup causes serious neurological problems that can be life-threatening in the newborn period.
How NKH Works in the Body
Glycine is a naturally occurring amino acid that serves as a chemical messenger in the brain and spinal cord. Normally, an enzyme system called the glycine cleavage system keeps glycine at safe levels by breaking it down. In babies with NKH, genetic mutations disable this enzyme system, so glycine accumulates throughout the body, especially in the central nervous system.
In the spinal cord and brainstem, glycine acts as an inhibitory neurotransmitter, meaning it slows down nerve signaling. When glycine floods these areas, it can suppress basic functions like breathing and muscle control. At the same time, glycine also activates a different type of receptor in the brain (the NMDA receptor), and overstimulation of these receptors can trigger seizures and damage developing brain tissue. This dual action is what makes NKH so devastating in newborns.
Signs in Newborns
The neonatal form is the most common presentation. Symptoms typically appear between 6 hours and 8 days after birth. Early signs include weak crying, poor sucking ability, and difficulty feeding. These problems tend to worsen rapidly over the first few days.
As glycine continues to build up, babies develop profound hypotonia (extremely low muscle tone, making them feel “floppy”), deep lethargy that can progress to coma, and life-threatening pauses in breathing called apnea. Persistent hiccups are a hallmark symptom that often appears before other signs and should raise suspicion for NKH. Seizures, particularly myoclonic jerks (brief involuntary muscle twitches), are common.
In one documented case, a full-term baby with normal birth weight and high Apgar scores began showing weak crying and sucking within hours of birth. By day three, the infant was lethargic, had lost all sucking and startle reflexes, and oxygen levels had dropped to 85%. That rapid progression from seemingly healthy to critically ill is characteristic of the condition.
Severe vs. Attenuated Forms
NKH falls along a spectrum. The severe form accounts for the majority of cases. Babies with severe NKH have very high glycine levels in their spinal fluid (above 230 µmol/L, compared to a normal level under 20). If they survive the newborn period, they typically go on to develop extreme intellectual disability, abnormal muscle stiffness (spasticity), ongoing seizures, and persistent feeding difficulties.
The attenuated form is less common and carries a somewhat better outlook. Glycine levels are elevated but lower, and the ratio of spinal fluid glycine to blood glycine stays below 0.08. Children with this form still face developmental challenges, but they may achieve more milestones than those with the severe form. Some forms of NKH can also appear later in infancy rather than immediately after birth, though this is rarer.
What Causes It Genetically
NKH is inherited in an autosomal recessive pattern, meaning a baby must receive a defective copy of the gene from both parents. Parents are typically carriers with no symptoms themselves. Three genes are independently linked to NKH: GLDC, AMT, and GCSH. Each encodes a different component of the glycine cleavage enzyme system. Mutations in GLDC are the most common cause, followed by AMT.
Because both parents must carry a mutation, the condition can appear without any family history. When both parents are carriers, each pregnancy carries a 25% chance of producing an affected child.
How NKH Is Diagnosed
Diagnosis requires measuring glycine levels in both the blood and spinal fluid at the same time. Elevated glycine in both, combined with an abnormally high spinal-fluid-to-blood glycine ratio, strongly suggests NKH. Plasma glycine alone does not predict how severe the condition will be. It is the spinal fluid level and the ratio that help doctors determine whether a baby has the severe or attenuated form.
Genetic testing confirms the diagnosis by identifying mutations in one of the three known genes. Brain imaging also plays a role, as it can show patterns of underdevelopment or damage consistent with NKH.
Treatment and What It Can Do
There is no cure for NKH. Treatment focuses on lowering glycine levels and managing symptoms. The primary medication is sodium benzoate, which helps the body clear glycine through an alternative pathway. It significantly reduces glycine levels in the blood and, to a lesser extent, in the spinal fluid, though it does not bring levels fully back to normal. Dosing depends on disease severity, with higher doses needed for the severe form.
For years, doctors also used NMDA receptor blockers (like dextromethorphan) on the theory that blocking the receptors glycine overstimulates would protect the brain. However, a critical reassessment of this approach found no clear clinical evidence that adding these drugs improves outcomes beyond glycine reduction alone, and there are concerns about potential adverse effects. Their routine use is now being reevaluated.
Seizure management, breathing support, and feeding assistance are central parts of care, especially in the newborn period. Many infants with severe NKH require mechanical ventilation early on.
Long-Term Outlook
The prognosis for NKH depends heavily on the form. In a study of 65 patients, roughly one-third died, with most girls dying during the neonatal period and boys having a median age of death of 2.6 years. Of the two-thirds who survived the newborn period, about 20% (mostly boys) eventually learned to walk and communicate using words or sign language. The reason for this gender difference is not fully understood.
Children with the attenuated form generally have a better prognosis, though developmental delays and some degree of intellectual disability remain common. Of 25 patients in the same study who lived past age three, 10 achieved the ability to walk and use words or signs. For families navigating this diagnosis, connecting with a metabolic specialist early gives the best chance of optimizing whatever level of development is possible.