Non-Ketotic Hyperglycinemia (NKH) is a rare genetic metabolic disorder characterized by the body’s inability to properly process glycine, a common amino acid. This condition affects approximately 1 in 76,000 newborns worldwide, though incidence can vary by population.
Understanding Non-Ketotic Hyperglycinemia
Non-Ketotic Hyperglycinemia, also known as glycine encephalopathy, is a disorder where abnormally high levels of glycine accumulate in the body, particularly in the brain and cerebrospinal fluid. Glycine is an amino acid, a fundamental building block of proteins, and also functions as a neurotransmitter. The “non-ketotic” aspect differentiates it from other conditions that cause elevated glycine levels alongside ketosis.
The core problem in NKH lies within the glycine cleavage system (GCS), a group of four enzymes primarily located in the mitochondria of cells. This system is responsible for breaking down excess glycine, a process crucial for the normal development and function of nerve cells. When the GCS does not function correctly, glycine builds up, leading to neurological issues. Excess glycine is known to overstimulate certain receptors in the brain, disrupting normal brain activity.
Genetic Basis and Inheritance
Non-Ketotic Hyperglycinemia is an inherited condition passed down through families in an autosomal recessive pattern. This means that a child must inherit two mutated copies of a specific gene, one from each parent, to develop the disorder. Parents who carry one mutated copy typically do not exhibit symptoms of NKH themselves.
The glycine cleavage system involves four protein components: P-protein, T-protein, H-protein, and L-protein. Mutations in the genes responsible for producing these proteins lead to NKH. The GLDC gene, which codes for the P-protein (glycine dehydrogenase), is implicated in about 80% of NKH cases. The AMT gene, responsible for the T-protein (aminomethyltransferase), accounts for most of the remaining cases, approximately 20%. Mutations in the GCSH gene, encoding the H-protein, are less common causes of NKH.
Recognizing the Signs and Diagnosis
The clinical presentation of Non-Ketotic Hyperglycinemia varies, ranging from severe forms that appear shortly after birth to milder, attenuated forms. In severe neonatal NKH, infants often experience profound lethargy, weak muscle tone (hypotonia), feeding difficulties, and life-threatening breathing problems, sometimes requiring ventilator support. Seizures are common and can be difficult to control, and affected infants may not achieve developmental milestones.
Attenuated forms of NKH present with similar but less severe symptoms, and can have a later onset, sometimes appearing in infancy or even childhood. Children with attenuated NKH may reach some developmental milestones, though often with delays, and can experience milder seizures.
Diagnosis of NKH typically begins with clinical suspicion based on these signs. Biochemical testing measures glycine levels in the blood plasma and cerebrospinal fluid (CSF). A significantly elevated CSF-to-plasma glycine ratio is a key indicator. Definitive diagnosis is confirmed through molecular genetic testing to identify mutations in the GLDC, AMT, or GCSH genes.
Current Management Strategies
Managing Non-Ketotic Hyperglycinemia focuses on alleviating symptoms and improving quality of life, as there is currently no cure. Pharmacological interventions aim to reduce glycine levels and modulate neurological activity.
Sodium benzoate is a medication used to lower glycine concentrations in the blood by binding to it and forming a compound that can be excreted. While it can normalize plasma glycine levels, it may not fully normalize CSF glycine levels.
Another key medication is dextromethorphan, an N-methyl-D-aspartate (NMDA) receptor antagonist. Glycine overstimulates NMDA receptors in the brain, and dextromethorphan works by blocking these receptors, which can help control seizures and improve neurological function. Other NMDA receptor blockers, such as ketamine, have also been explored.
Supportive care measures are also important for individuals with NKH. This includes managing seizures with anti-seizure medications, providing respiratory support for breathing difficulties, and ensuring adequate nutrition, often through specialized feeding methods. While these treatments can help manage symptoms, their effectiveness can vary significantly between individuals and forms of the disease. Early and consistent treatment is generally associated with better outcomes, particularly in attenuated forms of NKH.
Living with NKH: Outlook
The long-term outlook for individuals with Non-Ketotic Hyperglycinemia varies widely, depending largely on the severity of the condition and the effectiveness of early interventions. In severe neonatal forms, the prognosis can be challenging, with a high risk of significant developmental delays and intractable seizures. Many individuals with severe NKH do not achieve typical developmental milestones.
Individuals with attenuated forms of NKH may experience more varied developmental outcomes, sometimes learning to walk and interact, though often with delays. Ongoing research and advancements in supportive care continue to improve the quality of life for those affected. Specialized medical care and therapies are typically required throughout an individual’s life to manage symptoms and support development.