Jacqueline Kirby NKH Funding Project

Glycine Encephalopathy

NKH

General Discussion

Non-ketotic hyperglycinemia (NKH) is a rare, genetic, metabolic disorder caused by a defect in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of glycine in the body's tissues and fluids. There is a classical form of NKH and a variant form of NKH. The classical form is then further divided into severe disorder or an attenuated form (mild form).

Signs & Symptoms

The severe classic form of NKH typically presents in the first week of life with low muscle tone, lethargy, seizures, coma, and apnea requiring ventilator support. The ventilator is typically needed for a period of 10-20 days before the apnea resolves. A portion of individuals with severe classical NKH die during the neonatal period, often due to withdrawal of intensive care supports. All children with severe classical NKH who survive the neonatal period have severe developmental delay. Most individuals do not reach milestones past those reached by the typical 6-week-old infant. Seizures gradually worsen and can be difficult to control. Feeding difficulties and orthopedic problems can occur. Airway maintenance becomes poor over time due to low muscle tone, and is often the cause of death.

Individuals with attenuated classic NKH can present in the neonatal period or later in infancy. Presentation in the neonatal period resembles that of severe classic NKH. Those who present in infancy can have low muscle tone, lethargy, and seizures. Individuals with attenuated classic NKH have variable developmental progress. Developmental delays can range from mild to profound. They can often walk and achieve various motor skills. They often have hyperactivity and behavioral problems.

The clinical picture of individuals with variant NKH is rapidly evolving. Presentation varies depending upon what gene is mutated and the specific mutation itself. Particular symptoms can include: problems with spasticity or balance, problems with the nerve of the eye (optic neuropathy), problems with the white matter of the brain, heart weakness, increased resistance to blood flow in the lungs, accumulation of acid in the blood, loss of skills that the child had achieved, or seizures. Most children have only some of these problems.

Causes

Classic NKH is caused by genetic variants (mutations) in the genes that encode the components of the glycine cleavage enzyme system. This enzyme system is responsible for breaking down the amino acid glycine in the body. When it is not working properly, glycine accumulates in the body, resulting in the symptoms associated with NKH.

The glycine cleavage enzyme system is composed of 4 proteins, the P-protein encoded by the GLDC gene, the H-protein encoded by the GCSH gene, the T-protein encoded by the AMT gene, and the L-protein. Mutations in GLDC or AMT cause classic NKH. The majority of individuals with classic NKH have mutations within the GLDC gene. No mutations have been identified in the GCSH gene.

Individuals with deficient enzyme activity, but no mutation in GLDC or AMT, have variant NKH. Many genes have been described in variant NKH including LIAS, BOLA3, GLRX5, NFU1, ISCA2, IBA56, LIPT1 and LIPT2.

NKH is inherited in an autosomal recessive inheritance pattern, meaning that an individual must have pathogenic variants in both copies of the causative gene in order to be affected. Individuals with a pathogenic variant in only one copy of the gene are carriers for the disorder, and are not affected themselves, but could potentially have an affected child if their partner is also a carrier. If both parents are carriers for NKH, then there is a 1 in 4 chance, with each pregnancy, of the child being affected with NKH.

Affected Populations

The incidence of NKH is predicted to be approximately 1:76,000. NKH can occur in individuals of any ancestry.

Related Disorders

Symptoms of the following disorders can be similar to those of non-ketotic hyperglycinemia. Comparisons may be useful for a differential diagnosis:

Ketotic hyperglycinemia: propionic acidemia, methlymalonic acidemia, isovalerica acidema and B-ketothiolase deficiency. These patients have elevated glycine due to interference with the glycine cleavage enzyme system, but do not resemble NKH clinically.

Hyperglycinuria: familial iminoglycinuria and benign hyperglycinuria. These patients have elevated glycine in urine.

Disorders of pyridoxal-phosphate, such as pyridoxal-phosphate dependent encephalopathy. These children resemble NKH and can 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 NKH: Some children with severe injury to the brain have temporarily elevated glycine levels. They do not have a genetic deficiency in the glycine cleavage enzyme system. Their glycine levels come down spontaneously as they recover from the injury. Hypoxic-ischemic injury is one of the more common reasons for this.

Some children have been identified on newborn screening as having very elevated levels of glycine in blood. They have no symptoms. They do not have a deficiency in the glycine cleavage enzyme activity or have mutations in GLDC or AMT. They remain asymptomatic. The cause for this phenomenon is currently unknown.

Diagnosis

Cerebral spinal fluid (CSF) and plasma glycine levels are used in the diagnosis of NKH. Deficient enzyme activity causes elevated glycine levels in plasma and CSF, and an elevated CSF:plasma glycine ratio. High glycine levels in plasma and urine are not exclusive to NKH. Increased CSF glycine is highly indicative of NKH, however contamination of CSF with blood or serum can cause a false elevation of CSF glycine. CSF glycine is the preferred diagnostic test. Molecular analysis is an excellent confirmatory test. With sequencing and deletion/duplication analysis, 98% of alleles are detected. Brain MRI imaging can also be helpful because there is a specific pattern of changes seen in individuals with NKH.

Prenatal diagnosis is available when familial mutations are known.

Standard Therapies

Treatment

There is no curative treatment for NKH. However, there are treatments that can improve outcomes.

Sodium benzoate is used to reduce serum glycine levels. Benzoate binds to glycine in the body to form hippurate, which is excreted in the urine. This treatment reduces seizures and improves alertness. Plasma glycine levels must be monitored closely to ensure sodium benzoate is at an effective and non-toxic level.

Dextromethorphan is commonly used to reduce seizures and improve alertness. Dextromethorphan binds to NMDA receptors in the brain. These receptors are over-stimulated in individuals with NKH due to increased glycine levels in the brain. Glutamate is the neurotransmitter that predominately binds to these receptors. Dextromethorphan binds to the NMDA receptors, blocking glutamate from binding to the receptor. Ketamine is another NMDA receptor blocker that is also used. In patients with attenuated NKH, use of dextromethorphan can help with attention and chorea, and if treated early together with benzoate, can improve development and seizures.

Seizure management in individuals with severe classic NKH is difficult and usually requires multiple anticonvulsants. Valproate is not recommended for patients with NKH as it inhibits the residual glycine cleavage enzyme activity. Vigabatrin should rarely be used as many children with NKH have had adverse reactions to it.