ntroduction:
Nonketotic hyperglycinemia is a very rare clinical condition occurring as a genetic defect due to an error in the glycine (an amino acid present in the body) metabolism. Due to a breakdown or defect in the glycine enzyme system, patients lose the capacity to breakdown glycine, resulting in the accumulation of glycine throughout the body. This glycine buildup mainly occurs in the brain and the spinal cord, which, along with the primary clinical signs, show long term symptoms that are mostly neurological in origin. Although the exact cure for non ketotic hyperglycinemia is not known, advances in science are gradually reducing the associated diseases that accompany this condition. However, early diagnosis and treatment of this condition play a crucial role in the long term outcome of non ketotic hyperglycemia.
What Are the Causes of Nonketotic Hyperglycinemia?
Non ketotic hyperglycinemia is a clinical condition occurring due to a genetic defect in the intrauterine stage. The genes that are involved are the glycine decarboxylase (GLDC) and aminomethyltransferase (AMT) genes, which are usually involved in encoding components of proteins in the glycine pathway, reducing the activity of the enzyme. Here, glycine is the amino acid present in the body that mainly functions as an inhibitory neurotransmitter and also as a co-agonist causing an excitation modulator of the N-methyl-D-aspartate also called glutamatergic receptors. The excess activation of these receptors results in potential injury to the neurons or the axons, causing impaired nerve formation. As the glycine production and pathway are affected in nonketotic hyperglycinemia, there is an increased rate of sedimentation of glycine in the body. These pathological changes begin in the intrauterine life, causing irreversible brain damage induced by the glycine pathway, which becomes more evident when presented in the patient during the later stages of life.
How Commonly Is Nonketotic Hyperglycinemia Seen?
Nonketotic hyperglycinemia is a rare genetic disorder with an incidence of one in seventy-six thousand people globally. Usually, the incidence of this disorder is between one in twelve thousand and one in sixty three thousand newborns per locality or geographical region. The incidence of this condition is not particularly limited to any race or culture of origin, although a slight increase is seen in the white population or their descendants.
How Is Nonketotic Hyperglycinemia Seen Clinically?
As nonketotic hyperglycinemia is a genetic condition, careful evaluation and examination are of great importance. Care should be taken while extracting the complete case history from patients, as the condition is visible from birth. The clinical symptoms that are to be examined are signs of lethargy, poor eating habits, hypotonia, or decreased muscle tone, the presence of refractory seizures, brain damage, or encephalopathy, or sleep apnea (a clinical condition characterized by very low or no breathing during sleep). Assessments are done for growth and development along with diet history. Knowing the patient's history also plays a crucial role, and the incidence of stillbirth or neonatal death due to the unknown origin and history of consanguineous marriages is taken into consideration. The other clinical features include hiccups, irregular breathing, respiratory failures, and loss in motor and muscle tonicity.
How Is Non Ketotic Hyperglycinemia Evaluated?
The evaluation of nonketotic hyperglycinemia is done by systemic and laborigraphic assessments. The test usually indicated for this scenario is a complete blood count.
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Complete Blood Count (CBC): The complete blood count along with differential diagnosis assesses levels of blood glucose, serum creatinine, uric acid, urea nitrogen, electrolytes, ammonia levels, along with arterial blood gas and liver enzymes.
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CSF to Plasma Glycine Ratio: The glycine levels of the brain and spine is done by evaluating the CSF extracted from the spine and brain.
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Magnetic Resonance Imaging: The magnetic resonance imaging is used to examine the soft tissues using magnetic wave frequency. It is used to examine the brain in the infratentorial region or the posterior region during or before three months of age.
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Electroencephalogram: Electroencephalogram is a test used to test the electric conduction of the brain. This is indicated if the patient shows or has a history of seizures.
The other tests that are rarely indicated are brain magnetic resonance spectroscopy, which analyzes the enzyme activity in the brain and spinal cord, and molecular genetic testing.
How Is Non Ketotic Hyperglycinemia Treated?
The treatment of nonketotic hyperglycinemia aims to reduce the serum glycine concentration by reducing the activity of receptor sites by activating sodium benzoate and using N-methyl-D-aspartate as an antagonist at the sites that, in turn, decrease the binding of glycine. These conventional treatments evidently reduce the incidence of seizures, thus preventing any damage to neurological development.
Periodic checkups and an overall general examination, including bone growth to rule out hip dislocation or scoliosis, eye checkups for ruling out blindness in the cortex, developmental disorders, hypertension in the lungs, heart health, and heart and gastric health, are all done along with nutritional intake. The patient is also put on anti-epileptic drugs that prevent seizures. Surgical interventions are rarely preferred if needed, which are done by stimulating the vagus nerve.
What Are the Conditions Resembling Non Ketotic Hyperglycinemia?
There are various genetic conditions that resemble non ketotic hyperglycinemia; however, there are a few clinical features that resemble this condition, and those features are:
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Intracranial hemorrhage (bleeding within the skull).
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Thrombosis (blood clot).
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Hypoxia (decrease oxygen levels in the system).
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Neonatal epilepsy syndromes - A group of diseases that are characterized by frequency of seizures in newborns.
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Sepsis - Body’s reaction to a severe case of infection.
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Congenital brain maldevelopment - Improper brain development during the intrauterine stage of life.
Some of the factors that interfere with the diagnosis of non ketotic hyperglycinemia and alter the outcome are: medications, starvation, use of glycine rich fluids, artificial or wrong evaluation due to various sampling methods, hyperglycinemia (increase in blood glycine levels), intracerebral hemorrhage (bleeding within the brain), ischemia (a clinical condition characterized by lack of oxygen and blood supply to the parts of the body), or an immature glycine cleavage system (underdeveloped protein breakdown system). The conditions resembling nonketotic hyperglycemia are:
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Organic Acidurias - This is a metabolic disorder arising due to defects in the carbohydrate, fat and protein metabolic pathways.
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GLYT1 Encephalopathy - It is an acquired metabolic disease characterized by an increase in glycine levels.
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Lipotate Deficiency - A condition characterized by the deficiency of lipotate, an enzyme used for the conversion of lipoic acid.
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Affected Intra Cobalamin Metabolism - Defect in the cobalamin metabolism, where cobalamin is also known as vitamin b12 which is a fat soluble vitamin.
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Pyridoxine Dependent Epilepsy - It is a clinical condition characterized by onset of seizures from infancy or even before birth.
What Is the Outcome of Non Ketotic Hyperglycinemia?
The outcome or prognosis of nonketotic hyperglycemia depends on the degree of discrepancy in the glycine cleavage enzyme's systemic activity. The condition, when left untreated, may have a poor outcome in children, as they may go into respiratory distress during sleep. However, patients showing delayed symptoms of this condition, when diagnosed early and with proper treatment, show a very good prognosis.
What Are the Complications of Non Ketotic Hyperglycinemia?
The complications of non ketotic hyperglycinemia are:
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Respiratory failure.
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Epilepsy.
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Pulmonary hypertension (increased pressure in the lungs).
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Difficulty in swallowing.
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Dysmotility.
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Hip dislocation.
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Scoliosis - A clinical condition characterized by abnormal curvature of spine.
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Cortical blindness.
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Lethargy.
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Encephalopathy - It is a disease of the brain that alters the brain’s structure and function.
Conclusion:
Non ketotic hyperglycinemia, as discussed above, is a rare genetic condition that causes more deposition of glycine in the system due to a defect in the gene that breaks down the glycine, causing an elevated blood sugar level. It is seen in children commonly but is also seen in adults as a late onset. Although the disease can be stressful, especially in children, advances in medicine have effectively shown to reduce the occurrence of this disease with a good prognosis and an efficient lifestyle. And in order to achieve this, early and periodic checkups are very important.
