Hyperglycinemia refers to abnormally high levels of the amino acid glycine in the blood and other body fluids. The most well-known and clinically significant form is nonketotic hyperglycinemia (NKH), also called glycine encephalopathy, a rare inherited disorder in which a faulty enzyme system allows glycine to build up in the brain, spinal fluid, blood, and urine. Because glycine plays a role in nerve signaling, this buildup damages the developing brain, often severely. NKH typically appears in the first days of life and carries a serious prognosis, though milder and later-onset variants exist and can look quite different.
The Glycine Cleavage System and Why It Matters
Glycine is one of the simplest amino acids your body uses. Under normal circumstances, an enzyme complex called the glycine cleavage system breaks glycine down inside cells, converting it into smaller molecules the body can use for other purposes. This system sits on the inner membrane of mitochondria and consists of four protein components: P-protein (which contains a vitamin B6-related cofactor), T-protein (which handles a folate-dependent reaction), H-protein (which shuttles intermediate molecules), and L-protein (a shared enzyme also used in other pathways).1PubMed Central. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia In NKH, mutations cripple one of the first three components, so glycine cannot be properly broken down. It accumulates everywhere, but the consequences in the brain are by far the most devastating.
What Causes NKH
NKH is an autosomal recessive condition, meaning a child must inherit a defective copy of the relevant gene from each parent. Three genes code for the three specific components of the glycine cleavage system: GLDC (which encodes P-protein), AMT (T-protein), and GCSH (H-protein).2PubMed. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia Mutations in GLDC account for the majority of cases, with AMT mutations making up most of the remainder. Mutations in GCSH are quite rare. Parents who each silently carry one faulty copy have a one-in-four chance with each pregnancy of having an affected child.
One complication in carrier screening deserves attention. Expanded genetic carrier panels, the kind increasingly offered alongside fertility treatments, do not always flag so-called “variants of uncertain significance” (VUS). In at least one documented case, a couple undergoing IVF had carrier screening: the father was identified as carrying a known disease-causing GLDC variant, but the mother’s variant was classified as uncertain and left out of the report entirely. Their twins were born with severe NKH. Subsequent analysis showed the mother’s variant was likely harmful, and that determination could have been made before the pregnancy.3Genetics in Medicine Open. Missed opportunity for preconception and prenatal diagnosis in nonketotic hyperglycinemia: a case report Cases like this underscore the importance of thorough genetic counseling, especially when one partner is already known to carry a pathogenic variant.4PubMed Central. Severe Nonketotic Hyperglycinemia in Twins Caused by GLDC Variants: The Importance of Accurate Prenatal Variant Interpretation, Counseling, and VUS Disclosure
How Excess Glycine Harms the Brain
Glycine has a dual role in the nervous system. In the spinal cord, it acts as an inhibitory signal, calming nerve cells down. But in the brain, glycine also functions as a co-activator of a specific type of receptor called the NMDA receptor. Under normal conditions, small amounts of glycine help these receptors function in learning and development. When glycine floods the brain in NKH, it pushes NMDA receptors into overdrive, producing dangerous levels of nerve-cell excitation. Laboratory studies have shown that high glycine concentrations cause marked hyperexcitability and neurotoxicity in brain tissue, and that blocking NMDA receptors prevents this damage.5PubMed. Glycine causes increased excitability and neurotoxicity by activation of NMDA receptors in the hippocampus
This NMDA-driven excitotoxicity is not the whole story, though. Accumulating evidence from animal and human studies points to oxidative stress and disrupted energy production in brain cells as additional mechanisms driving brain injury in NKH.6PubMed. The Role of Excitotoxicity, Oxidative Stress and Bioenergetics Disruption in the Neuropathology of Nonketotic Hyperglycinemia The combination of overstimulated nerve cells, free-radical damage, and failing cellular energy supplies helps explain why the brain injury in classic NKH is so rapid and so severe.
Symptoms of Classic Neonatal NKH
The neonatal form is the most common presentation. Symptoms usually appear within the first few days of life, sometimes within hours of birth. Early signs include poor feeding, inability to suck, lethargy, and profound floppiness (hypotonia). Without intervention, the baby can progress rapidly to deep coma, breathing failure (apnea), and death. Seizures are common, particularly myoclonic seizures, and hiccups are a frequently noted early feature.7PubMed Central. Neonatal Nonketotic Hyperglycinemia: A Severe Case With Prenatal Indicators and Comprehensive Review of Recognition and Management In one single-center case series, the median age when symptoms first appeared was 8 days, seizures started at a median of 18 days, and accurate diagnosis took an average of nearly four months.8Molecular Genetics and Metabolism. Nonketotic hyperglycinemia: Clinical range and outcome of a rare neurometabolic disease in a single-center That gap between symptom onset and diagnosis is sobering, given how quickly the brain damage accumulates.
Attenuated and Late-Onset Forms
Not every case looks like the classic neonatal version. Attenuated NKH is milder and may not become obvious until infancy or early childhood. Rather than the devastating neonatal picture, children with attenuated forms can present with developmental delays, movement disorders such as chorea, and learning difficulties. Two siblings reported with the attenuated form had global developmental delay and involuntary movements; brain imaging showed thinning of the corpus callosum, and genetic testing confirmed compound heterozygous variants in GLDC.9PubMed Central. Attenuated form of Glycine Encephalopathy: An Unusual Cause of Neurodevelopmental Disorder These milder cases may go unrecognized for years because the symptoms overlap with many other causes of developmental problems.
Genuinely late-onset NKH is rare and may look nothing like the neonatal form. A two-year-old girl with previously normal development presented with an acute gait disturbance that progressed to severe spastic diplegia and white-matter changes on brain imaging.10PubMed. Late-onset nonketotic hyperglycinemia with leukodystrophy and an unusual clinical course In an even later case, a 15-year-old boy was found to have progressive vision loss and spinocerebellar degeneration along with elevated glycine levels.11PubMed. Late-onset nonketotic hyperglycinemia and spinocerebellar degeneration These unusual presentations suggest the condition is probably underdiagnosed in older children and adolescents.
How NKH Is Diagnosed
The cornerstone of biochemical diagnosis is measuring glycine in both blood plasma and cerebrospinal fluid (CSF), then calculating the ratio between the two. In classic neonatal NKH, CSF glycine and the CSF-to-plasma ratio are very high.12Molecular Genetics and Metabolism. Nonketotic Hyperglycinemia (Glycine Encephalopathy): Laboratory Diagnosis A CSF-to-plasma glycine ratio above 0.08 is generally considered suspicious, and research has refined this further. One study found that a CSF glycine concentration above about 117 µmol/L and a ratio at or above 0.15 were highly specific for severe NKH, while a ratio at or below 0.09 and symptom onset after three months of age were sensitive indicators of the attenuated form. A ratio threshold around 0.128 helped distinguish between severe and attenuated disease in cases that fell into an overlapping zone.13PubMed. Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia
There is a catch, however. In milder or atypical cases, the CSF glycine and the ratio may be completely normal. Two siblings with the clinical features of attenuated NKH had normal CSF glycine values, meaning clinicians who rely solely on the CSF ratio can miss the diagnosis.14PubMed. Atypical nonketotic hyperglycinemia with normal cerebrospinal fluid to plasma glycine ratio When biochemistry is ambiguous, molecular genetic testing of GLDC, AMT, and GCSH becomes the definitive diagnostic tool.
Brain Imaging Findings
MRI of the brain shows characteristic patterns that can support the diagnosis and hint at severity. In infants younger than three months with classic NKH, restricted diffusion (a marker of acute tissue injury) appears in specific tracts including the posterior limb of the internal capsule, the anterior brainstem, and the cerebellum. This particular pattern is absent in transient NKH, making it useful for distinguishing the two. In older infants, the restricted diffusion spreads to involve white matter throughout the brain.15PubMed. Brain imaging in classic nonketotic hyperglycinemia: Quantitative analysis and relation to phenotype
Other consistent MRI findings include progressive brain-volume loss that can be seen as early as four days after birth, thinning of the corpus callosum (found in virtually all patients), and delayed or absent myelination of white-matter tracts in older infants.16PubMed Central. Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations More advanced imaging techniques have also revealed diffuse abnormalities in white-matter fiber tracts throughout the brain.17PubMed. Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging
Distinguishing NKH from Other Causes of High Glycine
Not all high-glycine states are NKH, and sorting out the cause matters for treatment and prognosis. The most important distinction is between nonketotic and ketotic hyperglycinemia. In NKH, glycine is elevated but there are no ketones in the blood or urine. In ketotic hyperglycinemia, which is caused by organic acid disorders such as propionic acidemia or methylmalonic aciduria, patients have both elevated glycine and elevated ketones along with abnormal organic acid profiles.18Molecular Genetics and Metabolism Reports. Concurrent non-ketotic hyperglycinemia and propionic acidemia in an eight year old boy Checking urine organic acids is a straightforward way to tell the two apart.
Another important mimic is transient neonatal hyperglycinemia. These babies present with seizures and elevated glycine that looks identical to classic NKH in the first weeks of life, but the glycine levels normalize on their own, typically within about six weeks. The seizures improve as the glycine drops, and neurological development is usually normal afterward.19PubMed. Transient neonatal hyperglycinemia The prognosis is dramatically better than classic NKH, so recognizing this possibility is crucial. Most patients with the transient form show normal development, in stark contrast to the severe neurologic disability seen in classic NKH.20PubMed. Transient nonketotic hyperglycinemia: two case reports and literature review The early MRI findings described above, particularly the pattern of restricted diffusion, can help clinicians distinguish transient from classic disease before the biochemistry resolves on its own.
Current Treatment Approaches
There is no cure for NKH, and treatment options remain limited. The primary strategy is reducing glycine levels in the blood and brain. Sodium benzoate is the main drug used for this purpose: it binds to glycine in the body, forming hippuric acid that is then excreted in the urine. High-dose benzoate treatment aimed at normalizing plasma glycine has been shown to reduce seizures and increase alertness.21PubMed. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia The dose needed varies from patient to patient because each individual’s glycine pool is affected differently depending on the severity of the enzyme deficiency and dietary glycine intake. Clinicians track the relationship between benzoate dose and hippuric acid excretion to calibrate therapy.22PubMed. Excretion of hippuric acid during sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia
The second pillar of traditional treatment has been NMDA receptor blockers, specifically dextromethorphan (a cough suppressant at lower doses) and ketamine. The rationale was straightforward: if excess glycine overstimulates NMDA receptors, blocking those receptors should reduce the damage.23PubMed Central. Nonketotic Hyperglycinemia: Insight into Current Therapies However, a recent critical reassessment has challenged this entire approach. Researchers have pointed out that NMDA receptors also have another natural activator, D-serine, which turns out to be markedly decreased in NKH. This could mean the receptors are actually underactivated in some respects, not just overactivated. Clear clinical evidence that dextromethorphan or ketamine adds any real benefit beyond glycine reduction alone has not been documented, and there are emerging concerns about adverse effects from long-term use.24PubMed. The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment This is an area where clinical practice may shift in coming years as the evidence is reexamined.
The Valproate Warning
One practical point that clinicians and families should be aware of: valproate (valproic acid), a commonly prescribed anti-seizure medication, can paradoxically worsen seizures in children with NKH. In reported cases, seizure frequency increased after valproate was started. In fact, a paradoxical worsening of seizures on valproate can itself be a diagnostic clue pointing toward NKH.25PubMed. Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia Valproate inhibits an enzyme involved in glycine metabolism, which can further raise glycine levels, exactly the opposite of what you want in NKH.
Dietary Strategies
Beyond pharmacological approaches, dietary modification plays a role. Glycine-restricted diets have been used to limit the dietary contribution to the glycine pool. More recently, ketogenic diets have been studied as an alternative. A comparative study found that while neither a glycine-restricted diet nor a ketogenic diet significantly changed motor function scores, swallowing ability, or plasma glycine levels, the ketogenic diet led to significantly reduced seizure frequency and decreased the need for anti-seizure medications. In the glycine-restricted diet group, seizure frequency actually increased over the study period.26PubMed. Clinical and laboratory outcomes of ketogenic versus glycine-restricted diet in nonketotic hyperglycinemia: A comparative study These findings suggest the ketogenic diet may offer additional seizure control, though it does not address the underlying metabolic defect.
Prenatal Diagnosis and Family Planning
For families who have already had a child with NKH and want to know the risk for future pregnancies, prenatal diagnosis is possible. The most reliable approach combines two methods: measuring glycine cleavage enzyme activity in a chorionic villus sample (a tiny piece of placental tissue taken early in pregnancy) and measuring glycine levels in amniotic fluid. In a series of 15 at-risk pregnancies monitored this way, the combined approach successfully identified three affected pregnancies and correctly cleared twelve unaffected ones.27PubMed. Prenatal diagnosis of non-ketotic hyperglycinaemia Molecular genetic testing, where the family’s specific mutations are already known, now provides an additional option with high accuracy.
Gene Therapy Research
Because NKH is caused by mutations in a single gene in most cases, it is a natural candidate for gene therapy. Preclinical work has shown promising results. In one study, researchers designed a viral vector (an AAV9-based delivery system) to carry a working copy of the GLDC gene into the liver and brain of mice that model NKH. Treated mice showed significant lowering of glycine in both plasma and brain tissue, along with normalization of the folate profile, which is disrupted when glycine cannot be broken down properly.28PubMed. AAV-mediated expression of mouse or human GLDC normalises metabolic biomarkers in a GLDC-deficient mouse model of Non-Ketotic Hyperglycinemia
A more recent study went further, using CRISPR-edited mice carrying a common human NKH mutation. A single dose of a similar AAV9 vector expressing GLDC provided complete protection against disease progression and death in these mice. The treatment also boosted the generation of astrocytes, a type of brain support cell, without triggering an inflammatory response.29PubMed Central. Gene therapy prevents disease and death from non-ketotic hyperglycinemia These are animal studies, and the leap from mouse models to safe, effective human treatment involves years of additional work. But the results represent the strongest reason for cautious optimism that has emerged for this disease in decades. For families living with NKH today, the prospect of a treatment that addresses the root cause rather than managing symptoms is a meaningful shift in the landscape, even if clinical trials remain on the horizon.