Nonketotic hyperglycinemia (NKH), also called glycine encephalopathy, is an autosomal-recessive disorder of the glycine cleavage system. Excess glycine accumulates in the brain and can cause neonatal encephalopathy, abnormal breathing, developmental impairment and epilepsy.
Severe neonatal NKH
Severe disease usually presents in the first days of life with progressive lethargy, hypotonia, poor feeding, apnoea and myoclonic or other seizures.
Some infants initially require ventilatory support.
Epilepsy
Seizures often become increasingly difficult to control during the first year.
EEG can evolve from burst suppression to multifocal epileptiform activity or hypsarrhythmia.
Attenuated NKH
Attenuated disease has a broader range of outcomes.
Some children develop later-onset seizures, movement abnormalities, developmental disability or episodic neurological deterioration while achieving considerably more developmental progress than those with severe neonatal disease.
Biochemical diagnosis
Glycine is elevated in both plasma and cerebrospinal fluid.
The relationship between CSF and plasma glycine concentrations helps distinguish NKH from secondary hyperglycinemia.
Genetics
Most NKH is caused by biallelic pathogenic variants in GLDC or AMT, with rarer involvement of other glycine-cleavage-system components.
MRI
Characteristic diffusion abnormalities can affect myelinated pathways in the neonatal brain.
Later imaging can show cerebral atrophy or other secondary changes.
Sodium benzoate
Sodium benzoate lowers circulating glycine by creating an alternative route of glycine disposal.
It can improve alertness and facilitate seizure control, particularly in attenuated NKH.
NMDA-receptor blockade
Excess glycine overstimulates NMDA receptors.
Dextromethorphan is used in some specialist protocols to reduce this effect, especially in attenuated NKH.
Limits of treatment in severe NKH
GeneReviews states that current treatment does not change the fundamental natural history of severe NKH developmental disability and intractable epilepsy.
Therapy can nevertheless improve alertness, comfort and seizure management.
Medicines to avoid
Valproate can increase blood and CSF glycine and may worsen seizure frequency.
Vigabatrin has been associated with rapid loss of function in some people with attenuated NKH, particularly when treating infantile spasms.
Ketogenic diet
Ketogenic dietary therapy has improved seizure control in some individuals.
It can substantially reduce the glycine pool, so sodium-benzoate dosing must be adjusted to avoid toxicity.
Why metabolic supervision is essential
Benzoate dosing is guided by glycine concentration, clinical severity and age.
Incorrect dosing can cause toxicity, particularly when diet or metabolism changes.
Development and supportive care
Severe NKH commonly requires feeding support, respiratory care, physiotherapy and management of spasticity, scoliosis and hip problems.
Inheritance
NKH is autosomal recessive.
Once familial variants are identified, carrier and reproductive testing are possible.
Worldwide access
Diagnosis requires paired plasma/CSF biochemistry and molecular testing, which can delay recognition in resource-limited systems.
The disorder should be considered in neonatal encephalopathy with unexplained glycine elevation.
The central point
NKH is a metabolic epilepsy caused by excess glycine, and treatment must address that biochemistry as well as the seizures themselves.
Related reading
Sources
Medical note: sodium benzoate and dextromethorphan regimens require specialist metabolic supervision.
Evidence checked: September 2026.