Glycine encephalopathy (GE), also known as non-ketotic hyperglycinemia (NKH), is a rare inherited metabolic disorder primarily affecting infants and children. It results from the body’s inability to properly break down the amino acid glycine, leading to serious neurological symptoms.
Understanding Glycine Encephalopathy
GE results from a defect in the glycine cleavage system (GCS), a multi-enzyme complex responsible for glycine catabolism. Normally, the GCS breaks down glycine into carbon dioxide and ammonia, primarily in the liver, brain, and placental tissue. When the GCS is deficient, glycine accumulates in body fluids and tissues, including the brain. This accumulation is particularly damaging in the brain, where glycine acts as a neurotransmitter. The disorder is inherited in an autosomal recessive manner, meaning a child must inherit two copies of a mutated gene (one from each parent) to develop the condition. Mutations in the GLDC and AMT genes are the most common causes, while GCSH gene mutations are rare.
Recognizing the Signs
The signs of Glycine Encephalopathy vary in severity and age of onset, leading to different classifications. The neonatal form, which is the most common and often severe, typically manifests within the first few days of life. Affected infants may exhibit profound lethargy, poor muscle tone (hypotonia), persistent hiccups, and breathing difficulties, including apnea that can be life-threatening. Myoclonic jerks and intractable seizures are also common features in this severe presentation. Infants who survive the neonatal period often experience profound intellectual disability and ongoing seizures.
The infantile form generally presents with developmental delays and milder seizures, which may respond better to treatment. Attenuated forms, appearing later in infancy or adulthood, are characterized by milder symptoms like developmental delays, hyperactivity, and movement disorders such as chorea, with variable developmental progress. The specific symptoms and their severity depend on the residual activity of the glycine cleavage system.
Diagnosing Glycine Encephalopathy
Diagnosis of Glycine Encephalopathy begins with clinical suspicion based on the observed symptoms. The presence of unexplained neurological symptoms like seizures, hypotonia, and lethargy often prompts further investigation. Biochemical tests are then performed to measure glycine levels in the blood plasma and, importantly, in the cerebrospinal fluid (CSF). A diagnosis is strongly suggested by elevated glycine levels in both blood and CSF, particularly an increased CSF-to-plasma glycine ratio. This disproportionate elevation in CSF is a distinguishing feature of GE compared to other conditions that might cause high blood glycine. Definitive diagnosis is typically confirmed through genetic testing to identify mutations in the GLDC, AMT, or rarely, GCSH genes, which encode components of the glycine cleavage system. Brain imaging, such as MRI, may also reveal characteristic findings, including abnormalities in brain structures like the corpus callosum, which can support the diagnosis.
Treatment and Care Strategies
Currently, there is no cure for Glycine Encephalopathy, so treatment focuses on managing symptoms and reducing glycine levels.
Pharmacological Interventions
Pharmacological interventions are a primary approach. Sodium benzoate is used to lower plasma glycine concentrations by binding to glycine, which is then excreted. Dosing of sodium benzoate varies depending on the disease severity, with higher doses typically needed for severe forms. Another pharmacological strategy involves N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan. Glycine acts as a co-agonist at NMDA receptors, and its accumulation can lead to overstimulation of these receptors in the brain, contributing to neurological symptoms like seizures. Dextromethorphan helps to block these receptors, aiming to ameliorate neurological symptoms and improve seizure control. While these medications can help manage the condition, their effectiveness can vary significantly among individuals.
Dietary Management
Dietary management also plays a role. Low-protein diets are sometimes used to reduce the intake of glycine and thus its accumulation. The ketogenic diet has also shown promise in some patients, particularly for controlling intractable seizures and potentially lowering glycine levels.
Supportive Care and Prognosis
Supportive care is also paramount, including antiepileptic drugs for seizure control and interventions for feeding difficulties like gastrostomy tube placement. Physical and occupational therapy are important to support developmental progress and manage issues like spasticity. The prognosis for individuals with Glycine Encephalopathy varies widely; it is generally poor for the severe neonatal form, with many patients experiencing profound intellectual disability and intractable seizures, while attenuated forms can have more favorable outcomes.