Hyperglycinemia is a rare, inherited metabolic disorder characterized by abnormally high levels of the amino acid glycine in the body’s tissues and fluids, particularly the brain. Glycine is a fundamental building block for proteins and also functions as a chemical messenger in the central nervous system. Classified as an inborn error of metabolism, a genetic defect prevents the body from correctly processing this substance. The excessive accumulation of glycine leads to serious neurological problems, which define the disorder.
Understanding the Biochemical Error
This condition is most commonly known as Nonketotic Hyperglycinemia (NKH), which distinguishes it from other metabolic disorders that cause elevated glycine levels alongside ketones in the urine. The fundamental problem in NKH is a deficient Glycine Cleavage Enzyme (GCE) system, normally responsible for breaking down excess glycine. The GCE complex is a multi-protein enzyme system found primarily in the liver and brain.
The enzyme complex consists of four main protein components, including the P-protein (Glycine Decarboxylase) and the T-protein (Aminomethyltransferase). A malfunction prevents the system from effectively converting glycine into simpler molecules. This failure causes glycine to build up throughout the body. The accumulation is particularly damaging in the central nervous system because excess glycine overstimulates neurotransmitter receptors, resulting in severe neurological symptoms.
Identifying the Clinical Presentation
The clinical presentation of Nonketotic Hyperglycinemia is highly variable, correlating with the remaining activity of the Glycine Cleavage Enzyme system. The most common and severe form is the neonatal onset type, appearing within the first few days of life. Affected newborns show progressive lethargy, profound hypotonia, lack of spontaneous movement, and life-threatening breathing difficulties, including apnea. Intractable seizures are also common.
A less common presentation is the attenuated form, which can have an infantile or later childhood onset and is associated with a milder enzyme deficiency. Infants with this form may present with hypotonia and developmental delay, often without the severe lethargy or coma seen in the neonatal type. Children with the attenuated form usually exhibit varying degrees of intellectual disability and behavioral issues, though they may achieve developmental milestones like walking. Seizures are often present but are less severe and more responsive to treatment.
Genetic Basis and Transmission
Nonketotic Hyperglycinemia is an autosomal recessive disorder, meaning an individual must inherit a mutated copy of the responsible gene from both parents to develop the condition. Parents who each carry one copy of the mutated gene are typically asymptomatic carriers. The genes most frequently implicated in NKH are GLDC and AMT, which provide instructions for making the P-protein and T-protein components of the Glycine Cleavage Enzyme system.
Mutations in the GLDC gene account for the majority (around 80%) of NKH cases. Defects in the AMT gene are responsible for the remaining cases, causing a similar clinical picture. The specific mutation determines the residual enzyme activity, which dictates the severity of symptoms. Since the disorder is recessive, there is a 25% chance of recurrence in each subsequent pregnancy for carrier parents.
Screening, Diagnosis, and Management Strategies
Diagnosis of Nonketotic Hyperglycinemia is typically initiated when a newborn presents with suggestive neurological symptoms or through newborn screening programs. The definitive biochemical diagnosis relies on demonstrating elevated glycine concentrations in both the plasma and the cerebrospinal fluid (CSF). The most telling diagnostic marker is the CSF-to-plasma glycine ratio, which is significantly elevated in NKH compared to other causes of hyperglycinemia.
Once biochemical markers suggest the diagnosis, molecular genetic testing of the GLDC and AMT genes is used to confirm the presence of pathogenic mutations. Brain imaging, such as an MRI, may also reveal characteristic abnormalities, particularly in the corpus callosum. While there is no cure for NKH, management strategies focus on reducing the toxic levels of glycine and controlling the resulting neurological symptoms.
Pharmacological Interventions
The primary pharmacological intervention involves administering sodium benzoate, a drug that conjugates with glycine to form hippurate, which can then be excreted in the urine. Dosing must be carefully managed, often ranging from 150 to 750 mg/kg per day, with the goal of reducing plasma and CSF glycine levels. Another treatment approach is the use of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan or ketamine, to block the overstimulated receptors in the brain. These medications help manage severe seizures and improve alertness, though they do not alter the long-term neurodevelopmental outcome of the severe form.
Supportive Care
Management also includes anti-epileptic drugs for seizure control. Supportive care, such as physical and occupational therapy, is used to address developmental delays and spasticity.