Nonketotic Hyperglycinemia (NKH), also known as Glycine Encephalopathy, is an inherited metabolic disorder. The condition is characterized by an excessive buildup of the amino acid glycine in the body’s tissues and fluids. This accumulation occurs because the body is unable to break down glycine efficiently, leading to toxic levels that disrupt normal central nervous system function. NKH is classified as an inborn error of metabolism, and its nonketotic designation distinguishes it from other metabolic disorders that cause high glycine levels accompanied by a buildup of ketones.
The Metabolic Failure Behind NKH
The core biochemical problem in NKH involves the failure of the enzyme complex known as the Glycine Cleavage System (GCS). This complex resides in the mitochondria of cells in organs like the liver and brain, and its normal function is to break down glycine. A deficiency in the activity of this system prevents the catabolism of glycine, causing it to accumulate throughout the body.
The resulting high concentrations of glycine are particularly damaging to the central nervous system because glycine functions as a neurotransmitter in the brain. Glycine acts as a co-agonist for the N-methyl-D-aspartate (NMDA) receptor, which is involved in excitatory signaling. When excessive glycine builds up, it over-stimulates these NMDA receptors, leading to chronic over-excitation that is toxic to neurons.
This excitotoxicity is responsible for the severe neurological symptoms characteristic of the disorder, including seizures and profound developmental delays. The degree of GCS enzyme deficiency directly correlates with the severity of the disease.
Clinical Manifestations and Disease Types
Nonketotic Hyperglycinemia presents with a wide range of clinical severity, categorized into severe and attenuated forms. The severe neonatal form is the most common presentation, with symptoms typically appearing within the first hours or days after birth. These infants rapidly develop profound lethargy, which can progress to a deep coma, accompanied by severe hypotonia.
Life-threatening complications often include apnea, requiring immediate ventilatory support. Infants who survive the neonatal period generally suffer from intractable seizures and profound intellectual disability.
The attenuated, or milder, forms of NKH have a later onset, often appearing after the first few months of life or into childhood. These individuals may initially present with less severe symptoms, such as developmental delays, spasticity, and seizures that are easier to control. The late-onset form, which can appear in older children or even adults, is the mildest, typically involving intellectual disability, behavioral issues, and motor coordination problems.
The Genetics of Nonketotic Hyperglycinemia
Nonketotic Hyperglycinemia is an autosomal recessive disorder, meaning a child must inherit two copies of a non-working gene to be affected. Both parents of an affected child are typically carriers, possessing one copy of the mutated gene without showing symptoms.
The defects are most commonly found in two genes that encode components of the Glycine Cleavage System. Mutations in the GLDC gene account for the majority of NKH cases, approximately 80%. The remaining cases are primarily due to mutations in the AMT gene.
For parents who are both carriers, there is a 25% chance with each pregnancy that their child will inherit two copies of the mutated gene and be born with NKH. This inheritance pattern is important for genetic counseling and family planning.
Diagnostic Procedures
The diagnosis of NKH focuses on measuring glycine concentrations in the body. Initial suspicion often arises from the clinical presentation, particularly the combination of neurological symptoms and the absence of ketosis.
A definitive diagnosis relies on simultaneously measuring glycine levels in the blood plasma and the cerebrospinal fluid (CSF). Glycine is normally present in both fluids, but in NKH, the levels are elevated. The diagnostic indicator is the ratio of glycine concentration in the CSF compared to the plasma.
A CSF-to-plasma glycine ratio greater than 0.08 is highly suggestive of classic NKH, whereas a normal ratio is typically below 0.04. This ratio indicates the disproportionate accumulation of glycine in the central nervous system. Genetic testing, involving sequencing of the GLDC and AMT genes, serves as a confirmatory step, identifying the specific mutations causing the GCS deficiency.
Treatment and Management Strategies
There is currently no cure for Nonketotic Hyperglycinemia, so treatment focuses on managing symptoms and reducing the toxic accumulation of glycine. The two main pharmacological approaches aim to mitigate the biochemical and neurotoxic effects of the disorder.
One primary strategy involves the use of sodium benzoate, a medication that acts as a glycine scavenger. When administered, sodium benzoate binds to the excess glycine, forming hippurate, which is then excreted in the urine. This process helps to lower the overall glycine concentration in the plasma and in the CSF.
The second approach targets the excitotoxicity caused by glycine’s action on NMDA receptors. Medications classified as NMDA receptor antagonists, such as dextromethorphan, are used to block these receptors. Dextromethorphan reduces the overstimulation of neurons, which can help in controlling seizures and potentially improving neurological function in some patients.
Supportive care is also a part of management, particularly for the severe neonatal form. This includes management of seizures with standard anticonvulsant medications and providing nutritional support, often through feeding tubes. Physical, occupational, and speech therapy are often required to help children achieve their developmental potential, though outcomes remain highly variable depending on the severity of the initial presentation.