The worldwide incidence of NKH is unknown. However, it has been studied in certain regions of the world. The birth incidence of NKH is 1:55,000 in Finland, 1:12,000 in an area of Northern Finland, and 1:63,000 in British Columbia, Canada.

NKH is caused by a deficiency in what is known as the glycine cleavage enzyme system (GCS or GCE). The GCS is an enzyme complex, responsible for breaking down glycine into smaller molecules. An enzyme complex is a collection of proteins that work together to speed up chemical reactions in the body, such as the breakdown of a large molecule into smaller products. The GCS is made up of four distinct proteins known as P-protein (pyridoxal phosphate containing glycine decarboxylase, GLDC), H-protein (lipoic acid containing), T-protein (tetrahydrofolate-requiring aminomethyltransferase, AMT), and L-protein (lipoamide dehydrogenase). 80% of affected individuals have a defective P-protein while 15% have a defective T-protein. H-protein defects rarely occur in NKH and L-protein defects are associated with a distinct condition. Each of these proteins is encoded by different genes. The P-protein is encoded by a gene known as GLDC, T-protein is encoded by a gene known as AMT, and H-protein is encoded by a gene known as GCSH. Mutations in these genes are responsible for the deficiency in their corresponding proteins, and thus, NKH. Although, in 5% of cases have both genes are normal and the underlying cause of the condition is unknown. NKH is an autosomal recessive disorder. Everyone receives one copy for each gene from their mother and one copy from their father. An autosomal recessive disorder means that both copies of the gene must be defective for NKH to present.

Mutations in either the AMT, GLDC, or GCSH genes leads to a glycine cleavage enzyme complex that is unable to breaking down glycine properly. As a result, glycine will build up in the body, causing damage to the brain and spinal cord, in particular, followed by intellectual disability, seizures, and breathing difficulties.

Symptoms of NKH vary depending on the onset and the severity of NKH. Importantly, NKH symptoms present as a continuous spectrum and may fall between the forms described here. In most affected individuals present NKH as neonates, out of which 85% develop the severe form and 15% develop the attenuated form. In individuals affected by the neonatal form, symptoms are observed within the first hours or days after birth. Symptoms include progressive lack of energy (lethargy), lack of muscle tone or resistant to stretch in muscle(hypotonia), sudden and involuntary muscle contraction (myoclonic jerks) which can lead to the temporary inability to breath (apnea), coma, and even death of untreated. Involuntary muscle contractions lead to apnea as muscles involved in breathing can also get involved. Affected individuals may need intubation and mechanical ventilation to facilitate breathing. Intubation refers to the placement of a flexible tube into the airways. A mechanical ventilation machine will then breathe for the affected individual through their intubation. It is important to note that the vast majority of affected individuals will regain their ability to breathe in a few weeks. Further intellectual disabilities and seizures may develop. Other less common symptoms and findings in the neonatal severe form includes potential brain malformation, cleft lip/palate, and malformed ears.

A smaller percentage of affected individual may present symptoms in infancy, out of which 50% develop the severe form and 50% develop  the attenuated form. There are differences between the infantile and the neonatal forms. Individuals affected by the infantile form do not exhibit the lack of energy (lethargy) and apnea observed in the neonatal form. However, they may have a history of low muscle tone or hypotonia. Muscle tone is the unconscious and low level of muscle contraction when they are at rest. Hypotonia is commonly known as the floppy baby syndrome as the affected infant’s muscles may feel abnormally soft or limp. The infantile form also presents with developmental delay and infantile-onset seizures.

Additionally, as described earlier, the severity of the condition plays a role in symptom presentation. Individuals who develop the severe form, have significant developmental delay. They may learn to smile, grasp objects, or sit and present with seizures that become more difficult to treat as they age. Other complications could be scoliosis which is the sideway curvature of the spine, as well as difficulty swallowing. Many affected individuals may develop what is known as spastic quadriparesis. This is a condition affecting all four limbs that is characterized by stiffness and muscle contraction that makes it difficult to move. In rare cases, club feet has also been found. Club feet describes a conditions where the feet are rotated inwards or downwards and the soles of the feet face each other.

Individuals who develop the attenuated form have less severe developmental delay but tend to be hyperactive. They are likely to learn to walk, interact with caregivers, have sign language, and attend special education classes. Seizures are still common but are easily treated.  They may exhibit choreic movement which is an abnormal, quick, and involuntary movement of the hands and feet. However, this has been associated with better prognostic outcome. Furthermore, episodes of severe lethargy might occur in these individuals.

There have been rare reports of individuals who develop a mild form of the condition. They have some developmental disability and may be able to attend normal schooling. They may or may not have seizures and could have  attention deficit and hyperactivity disorder (ADHD).

NKH may present as an atypical form that could range from mild symptoms presenting in late infancy to adulthood, to late-onset rapidly progressing severe form.

NKH is suspected when CSF glycine concentration, as well as the CSF-to-plasma glycine ratio is elevated. CSF, or the cerebrospinal fluid, is a fluid surrounding the brain and in the spinal cord that plays that protects these vital structures. Diagnosis is confirmed through a biopsy that shows diminished enzymatic activity of the glycine cleavage system in the liver. Affected individual often have no detectable enzymatic activity.

When NKH is clinically suspected, biochemical screening must be performed to measure the level of glycine in both plasma and CSF. If glycine levels are elevated in plasma and CSF, further confirmatory tests will be performed.

Genetic testing could further support diagnosis. Certain variations in GLDC, AMT, and GCSH genes are known to cause NKH. Commonly, all three genes are sequenced concurrently to identify possible genetic disease-causing variations.  

Finally, diagnosis can be confirmed using enzymatic measurement of glycine cleavage system in the liver. The liver tissue required for biopsy is obtained endoscopically. This procedure is a non-surgical technique where a thin flexible tube is used to obtain the sample required.

Measurement of glycine cleavage system enzymatic activity is the confirmatory diagnostic test for NKH.

The current treatment of NKH aims to reduce plasma concentrations of glycine and inhibit the binding of glycine to NMDA. As described earlier, glycine acts as a chemical messenger between nerve cells in the brain. It exerts its effects by binding to a receptor called NMDA (N-methyl D-aspartate).

Sodium benzoate is used to decrease plasma concentration of glycine; however, this treatment does not lower glycine levels in the CSF. Sodium benzoate increases alertness and can improve behavior in affected individuals with milder symptoms. Additionally, in patients with mild or attenuated forms, sodium benzoate diminishes lethargic episodes that are observed.

Another group of drugs used to treat NKH are NMDA receptor site antagonists. These are molecules that do not allow glycine to bind to the NMDA receptor, thus, inhibit its effects. In attenuated or mild forms, NMDA antagonists improve alertness and seizure control.

Additionally, standard anti-seizure drugs are not effective for neonates affected by NKH. However, the nature of the seizures change in older infants. Thus, some standard anti-seizure drugs may be used in older affected children to control seizures. Ketogenic diet as also shown variable effectiveness to control seizures. The ketogenic diet is a low-carb, high-fat diet used to control seizures. This diet increases the blood levels of a group of molecules known as ketones. Elevated levels of ketone bodies in the blood reduces the frequency of seizures.

Unfortunately, these treatments are usually ineffective in individuals with severe NKH. However, a vagal nerve stimulator has shown varying levels of success for control of seizures that are difficult to treat in the severe form. Vagal nerve stimulation is a procedure where a device is implanted in the body that stimulates a nerve called to vagus nerve. This procedure is used to treat seizures when other treatments have been ineffective.

The prognosis of NKH depends on a number of factors including the age at onset, presence or absence of brain malformations, and CSF and plasma glycine levels. However, generally the affected individuals with the neonatal form have poor outcomes and life expectancy compared to individuals affected by the infantile forms. The best outcome that has been reported in NKH is normal intelligence in affected individuals who exhibit residual glycine cleavage system enzymatic activity who obtained aggressive and early treatment. Residual enzymatic activity is seen in individuals who have a disease-causing variant in one of the associated genes; however, the variant leads to production of a protein that has enzymatic activity but lower than normal.

Valproate is an anti-seizure medication that is contraindicated in NKH because it increases blood and CSF glycine levels. This may lead to increased siezure frequency, lethargy, and coma.

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