Glycine encephalopathy: what is it, symptoms, treatment, prognosis

What is glycine encephalopathy?

Glycine encephalopathy (or non-ketotic hyperglycemia, abbr. NKG) Is a rare genetic metabolic disorder caused by a defect in the enzyme system that breaks down the amino acid glycine, resulting in the accumulation of glycine in tissues and body fluids. There is a classic form of NCG and a variable form of NCG. Also, the classic form is subdivided into a severe illness or a weakened (mild) form.

Signs and symptoms

The severe classic form of glycine encephalopathy usually manifests itself in the first week of life with low muscle tone, lethargy, seizures, coma and apnearequiring artificial ventilation support. A ventilator is usually required for 10 to 20 days before the apnea resolves. A proportion of people with severe classic NCH die in the neonatal period, often due to failure to support intensive care. All children with severe classical glycine encephalopathy who survived the neonatal period have severe developmental delay. Most people do not reach a milestone higher than that of a typical 6-week-old infant. The attacks gradually get worse and are difficult to control. Feeding difficulties and orthopedic problems may arise. Airway maintenance deteriorates over time due to low muscle tone and is often the cause of death.

Attenuated classical NKH may appear in the neonatal period or later in infancy. The manifestation in the neonatal period resembles severe classical NKH. Those who are sick in infancy may have low muscle tone, lethargy, and cramps. People with impaired classic glycine encephalopathy have variable developmental progress. Developmental delay can range from mild to severe. They can often walk and develop a variety of motor skills. They often have hyperactivity and behavior problems.

The clinical picture of people with variable NCH is changing rapidly. Representation varies depending on which gene is mutated and on the particular mutation itself. Specific symptoms may include: problems with spasticity or balance, problems with the optic nerve (optic neuropathy), problems with white matter brain weakness, increased resistance to blood flow in the lungs, acid build-up in the blood, loss of skills that the child has attained, or convulsions. Most children have only a few of these problems.

Causes

Classical glycine encephalopathy is caused by genetic variants (mutations) in genes that encode components of the glycine cleavage enzyme system. This enzyme system is responsible for the breakdown of the amino acid glycine in the body. When not working properly, glycine builds up in the body, leading to disease-related symptoms.

The enzyme system for cleaving glycine consists of 4 proteins, the P-protein encoded by the gene GLDC, H-protein encoded by the gene GCSH, T-protein encoded by the gene AMT, and L-protein. Mutations in GLDC or AMT cause classic NCG. Most people with classic NCH have mutations in the gene GLDC. In the gene GCSH no mutations were found.

In people with insufficient enzymatic activity, but without a mutation in GLDC or AMT, there is a variable form of glycine encephalopathy. The variable form of the disease is caused by the following gene mutations: LIAS, BOLA3, GLRX5, NFU1, ISCA2, IBA56, LIPT1 and LIPT2.

Glycine encephalopathy is inherited in an autosomal recessive mode of inheritance, which means that in order to get sick, a person must have pathogenic variants in both copies of the causative gene. Individuals with a pathogenic variant in only one copy of the gene are carriers of the disease and are not themselves affected, but could potentially have a sick child if their partner is also a carrier. If both parents are carriers of NKH, then with each pregnancy, the probability that the baby will be affected by NKH is 1 in 4.

Affected populations

The incidence of NKH is projected to be approximately 1 in 76,000. The disease can occur in people of any origin.

Symptomatic disorders

Symptoms of the following diseases may be similar to those of glycine encephalopathy (non-ketotic hyperglycemia, NKH). Comparisons can be useful for differential diagnosis:

• Ketotic hyperglycemia: Propionic acidemia, methylmalonic acidemia, isovalericacidema and B-ketothiolase deficiency. These patients have elevated glycine levels due to interference with the glycine cleavage enzyme system, but clinically they do not resemble NCG.
• Hyperglycinuria: familial iminoglycinuria and benign hyperglycinuria. These patients have elevated urinary glycine levels.
• Diseases of pyridoxal phosphatesuch as pyridoxal phosphate-dependent encephalopathy. The disease resembles NKH, patients may have elevated glycine levels. They lack active vitamin B6 (called pyridoxal phosphate), which is a necessary compound for the activity of the glycine cleavage enzyme.
• Transient NCG: Some children with severe brain injury have temporarily elevated glycine levels. They do not have a genetic deficiency in the glycine cleavage enzyme system. Their glycine levels drop spontaneously as they recover from injury. Hypoxic-ischemic injury is one of the most common causes of this.

When examining newborns, some children showed a very high level of glycine in the blood. They have no symptoms. They do not have a deficiency in glycine cleavage enzyme activity or a mutation in GLDC or AMT. They remain asymptomatic. The reason for this phenomenon is currently unknown.

Diagnostics

In the diagnosis of glycine encephalopathy, cerebrospinal fluid (CSF) levels and plasma glycine levels are examined. Insufficient activity of the enzyme causes an increased level of glycine in plasma and cerebrospinal fluid, as well as an increased ratio of glycine in cerebrospinal fluid and plasma. High levels of glycine in plasma and urine are not exclusive to the disease. An increased level of glycine in the cerebrospinal fluid is a strong sign of glycine encephalopathy, however Cerebrospinal fluid contamination with blood or serum can cause a false increase in glycine in the cerebrospinal liquids. Cerebrospinal fluid glycine is the preferred diagnostic test. Molecular analysis is an excellent confirmatory test. Through sequencing and analysis of deletions / duplications, 98% of alleles are found. An MRI of the brain can also be helpful because people with NCH have a certain pattern of changes.

Prenatal diagnosis is also available when familial mutations are known.

Standard treatments

There is no cure for glycine encephalopathy. However, there are treatments that can improve symptoms.

Sodium benzoate is used to lower serum glycine levels. Benzoate binds to glycine in the body to form hippurate, which is excreted in the urine. This procedure reduces cramps and enhances alertness. Plasma glycine levels must be carefully monitored to ensure sodium benzoate is at an effective and non-toxic level.

Dextromethorphan is commonly used to reduce seizures and improve focus. Dextromethorphan binds to NMDA receptors in the brain. These receptors are overstimulated in patients with NCH due to increased levels of glycine in the brain. Glutamate is a neurotransmitter that primarily binds to these receptors. Dextromethorphan binds to NMDA receptors, blocking the binding of glutamate to the receptor. Ketamine is another NMDA receptor blocker that is also used. In patients with weakened NCH, the use of dextromethorphan can help with attention and chorea, and with early treatment with benzoate, it can improve development and seizures.

Seizure management in people with severe classic NCH is difficult and usually requires multiple antiseizure medications. Valproate is not recommended for patients with glycine encephalopathy because it inhibits the activity of the glycine residual cleavage enzyme. Vigabatrin should be rarely used because many children with NKH have had adverse reactions to it.

Forecast

The prognosis depends on the severity of the disease. Most patients with neonatal or infantile forms have severe outcomes. In the neonatal form, early death sometimes occurs due to apnea. The prognosis for atypical cases varies.