Nonketotic Hyperglycinemia (NKH), sometimes called Glycine Encephalopathy, is a rare, inherited metabolic disorder that affects the body’s ability to process the amino acid glycine. This leads to a toxic accumulation of glycine throughout the body, particularly in the brain and cerebrospinal fluid (CSF). The disorder causes severe neurological problems that typically manifest shortly after birth, making it a serious, life-limiting diagnosis. It is classified as an inborn error of metabolism, meaning it interferes with specific chemical conversions necessary for normal bodily function.
Underlying Mechanism and Genetic Cause
Nonketotic Hyperglycinemia is caused by a defect in the Glycine Cleavage System (GCS), a multi-enzyme complex responsible for breaking down the amino acid glycine. This system performs a single, irreversible reaction that degrades glycine into carbon dioxide and ammonia within the mitochondria of cells. When one of the components of this system is non-functional, glycine cannot be properly metabolized and begins to build up in the body.
The deficiency in the GCS is traced back to mutations in specific genes that encode the protein subunits of the enzyme complex. The genes most commonly implicated are GLDC (Glycine Decarboxylase), which accounts for the majority of cases, and AMT (Aminomethyltransferase). A third gene, GCSH, which codes for the H-protein component of the system, is also rarely involved.
NKH is inherited in an autosomal recessive pattern, meaning a child must inherit a copy of the defective gene from both parents to develop the condition. The resulting accumulation of glycine is most damaging in the central nervous system, where glycine functions as a neurotransmitter. Excess glycine overstimulates receptors in the brain, leading to the severe neurological symptoms.
Clinical Presentation and Forms
The clinical presentation of NKH is highly variable but categorized into severe and attenuated forms, which differ significantly in their onset, severity, and long-term outcome. The most common form is the severe Neonatal Form, where symptoms begin within the first hours or days of life. Affected newborns display progressive lethargy, which can quickly lead to a profound coma, along with weak muscle tone, called hypotonia.
Life-threatening complications such as apnea (pauses in breathing) and difficult-to-control seizures are common in the severe neonatal form. Survivors of this initial, acute phase typically experience profound intellectual disability and lack developmental progress. Brain imaging, such as an MRI, in severe cases may reveal a smaller-than-average corpus callosum, the tissue connecting the two brain hemispheres.
A less common presentation is the Attenuated Form, which includes the Infantile and Late-Onset types, where symptoms begin later than the first few weeks of life. Individuals with the attenuated form demonstrate variable developmental progress and often have milder symptoms. While they may still experience developmental delay, they often achieve milestones like walking and can have seizures that are more treatable.
The Infantile Form typically presents between two weeks and three months of age with hypotonia and developmental delays, and about half of these cases progress to the severe outcome. The rare Late-Onset Form involves developmental delays and behavioral abnormalities. The severity of the condition correlates directly with the amount of residual activity remaining in the defective Glycine Cleavage System.
Diagnosis and Screening Protocols
Diagnosis of Nonketotic Hyperglycinemia begins with a suspicion based on the characteristic clinical signs, particularly the rapid neurological deterioration in a neonate. This is followed by a series of laboratory tests to confirm the biochemical markers of the disorder. The hallmark of NKH is the isolated elevation of glycine levels in both the blood plasma and the cerebrospinal fluid (CSF).
The most specific and reliable diagnostic test is the measurement of the CSF:plasma glycine ratio, which compares the glycine concentration in the fluid surrounding the brain and spine to the concentration in the blood. A ratio exceeding 0.08, drawn from simultaneously collected samples, is strongly indicative of NKH, as the normal ratio is much lower. This ratio is particularly informative because few other disorders cause such a disproportionate increase in the CSF.
Genetic testing is used to provide a definitive diagnosis by identifying pathogenic mutations in the GLDC, AMT, or GCSH genes. DNA sequencing confirms the specific gene defect, which can also help predict the likely severity of the condition. While some regions include NKH in their newborn screening programs by testing for high glycine in blood spots, this screening method has a high false-negative rate and requires confirmatory testing.
Management Strategies
Currently, there is no cure for Nonketotic Hyperglycinemia, so management focuses on reducing the toxic levels of glycine and controlling the severe neurological symptoms. The primary medication used to lower glycine is sodium benzoate, which works by binding to excess glycine in the blood to form hippuric acid, a compound that the kidneys can excrete. Doses are typically high and can normalize plasma glycine, although they only partially reduce the levels in the CSF.
A second line of treatment involves blocking the overstimulated N-methyl-D-aspartate (NMDA) receptors in the brain to counteract the neurotoxic effects of excess glycine. Dextromethorphan, often used as a cough suppressant, is the most common medication used for this purpose because it acts as an NMDA receptor antagonist. This combination therapy can lead to improved seizure control and some developmental progress in patients with the attenuated form.
Dietary management, specifically a low-glycine diet, is sometimes implemented, particularly in severe cases, to support the effects of sodium benzoate. Supportive care is necessary for neurological issues, which may include anti-epileptic drugs for seizures and physical therapy. Despite these interventions, the prognosis for the severe neonatal form remains poor, with patients showing no developmental progress, while the attenuated form offers a variable but better outcome.