Causes of High Glycine Levels
High levels of the amino acid glycine, a condition known as hyperglycinemia, are most commonly associated with a rare genetic metabolic disorder called Nonketotic Hyperglycinemia (NKH) or glycine encephalopathy. In NKH, a defect in the glycine cleavage system prevents the body from breaking down glycine properly, causing it to build up, especially in the brain.
The Role of Genetics
- Gene Mutations: The primary cause of NKH is mutations in the GLDC or AMT genes, which are responsible for producing the enzymes needed for glycine metabolism. Over 80% of NKH cases involve a mutation in the GLDC gene.
- Inheritance: NKH is an autosomal recessive disorder, meaning a child must inherit a mutated gene from both parents to be affected.
Other Potential Causes
While NKH is the most common cause, other situations can lead to excessively high glycine levels:
- Surgical Complications: Glycine-containing irrigation fluids used during certain procedures, like transurethral resection of the prostate (TURP), can be absorbed into the bloodstream. This can lead to acute glycine toxicity, a known side effect called TURP syndrome.
- Other Metabolic Disorders: Certain inborn errors of metabolism, such as some organic acidurias, can also cause elevated glycine, a phenomenon referred to as "ketotic hyperglycinemia".
Symptoms in Different Populations
High glycine levels manifest differently depending on the patient's age and the specific cause of the accumulation.
Symptoms in Infants (Neonatal NKH)
The most severe and life-threatening form of NKH typically begins within the first few days of life and is characterized by rapid neurological deterioration.
- Profound Lethargy: Infants may exhibit extreme sleepiness, poor feeding, and a weak cry, which can progress to a coma.
- Weak Muscle Tone (Hypotonia): This is a hallmark symptom, often accompanied by a lack of muscle strength.
- Breathing Difficulties: Life-threatening pauses in breathing (apnea) and irregular breathing are common and may require mechanical ventilation.
- Seizures: Intractable, difficult-to-control seizures and myoclonic jerks (sudden muscle twitches) are prominent features.
- Other Manifestations: Hiccups, swallowing difficulties, and subsequent profound intellectual disability are also observed in surviving infants.
Symptoms in Children and Adults (Attenuated or Late-Onset NKH)
In some cases, the condition is less severe, with symptoms appearing later in infancy or even adulthood.
- Developmental Delays: Learning difficulties, cognitive impairment, and delayed motor skills are common.
- Neurological Signs: Patients may experience a range of movement disorders, including poor coordination (ataxia), tremors, and chorea (involuntary jerking movements).
- Behavioral Problems: Hyperactivity, irritability, and other behavioral issues can present.
- Episodic Symptoms: Some individuals experience periods of severe lethargy or delirium, often triggered by illness.
Acute Glycine Toxicity Symptoms
For individuals experiencing acute toxicity from medical procedures, the symptoms are different and arise rapidly.
- Visual Disturbances: Transient blindness or blurry vision is a unique sign of this type of toxicity.
- Neurological Effects: Nausea, confusion, dizziness, and weakness are common.
- Cardiac Issues: The heart can be affected, with possible myocardial depression and changes in blood pressure.
Differential Diagnosis and Comparison
Because high glycine levels can be a sign of different conditions, a differential diagnosis is necessary. The distinction between ketotic and nonketotic hyperglycinemia is a critical step in guiding treatment and understanding prognosis. Proper diagnosis relies on careful clinical evaluation and specific laboratory tests, particularly the CSF/plasma glycine ratio.
| Feature | Nonketotic Hyperglycinemia (NKH) | Organic Acidurias (Ketotic Hyperglycinemia) |
|---|---|---|
| Cause | Genetic defects in the glycine cleavage system (GLDC, AMT genes). | Defects in metabolism of other organic acids (e.g., methylmalonic acidemia). |
| Associated Ketones | Absence of significant ketosis. | Presence of ketosis. |
| CSF/Plasma Glycine Ratio | Significantly elevated (typically >0.08). | Often normal, as the glycine accumulation is different. |
| Clinical Presentation | Primarily neurological symptoms, such as severe lethargy, hypotonia, and intractable seizures, especially in neonates. | Encephalopathy, metabolic acidosis, vomiting, and ketosis, often appearing in the neonatal period. |
Conclusion
Understanding what are the symptoms of high glycine levels is critical for early diagnosis, particularly in rare metabolic disorders like nonketotic hyperglycinemia. While the most severe presentations occur in newborns, leading to profound neurological and developmental issues, milder or later-onset forms also exist with a wide spectrum of cognitive and motor symptoms. High glycine can also occur acutely due to surgical complications, presenting with distinct visual and neurological signs. Anyone with concerns about these symptoms should seek immediate medical attention for proper diagnosis and management, as timely intervention can significantly influence outcomes. For more information on genetic metabolic disorders, consult resources like the National Organization for Rare Disorders (NORD).
