About nonketotic hyperglycinemia

What is nonketotic hyperglycinemia?

Nonketotic hyperglycinemia is an inborn error of metabolism characterized by the accumulation of large amounts of the amino acid glycine in blood, urine and, particularly, the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. There are four forms of this disorder: a relatively common neonatal form, an infantile form, a mild-episodic form, and a late-onset form.

What are the symptoms for nonketotic hyperglycinemia?

Coma symptom was found in the nonketotic hyperglycinemia condition

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.

What are the causes for nonketotic hyperglycinemia?

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.

What are the treatments for nonketotic hyperglycinemia?

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.

What are the risk factors for nonketotic hyperglycinemia?

A high level of glycine in the body leads to a condition called nonketotic hyperglycinemia that primarily affects the nervous system. The disease onset occurs a few months after birth and has two forms: attenuated and severe. Early signs and symptoms are lethargy (which worsens over time and can lead to coma), life-threatening breathing difficulties, and weak muscle tone. The children who survive the early symptoms such as feeding difficulties, abnormal muscle stiffness (spasticity), profound intellectual disability, and seizures that are difficult to control. The manifestations are similar in both types, but the attenuated form is milder than the severe one.
Risk factors
1. The condition is caused by mutations in the genes GLDC and AMT that codes for the synthesis of glycine-cleaving enzymes. It can be inherited from parents in an autosomal recessive mode.
2. An affected child receives one copy of the mutations from each parent, who are either affected or a carrier.
3. Parents who are carriers do not show any signs and symptoms of hyperglycinemia.
4. Thus, the risk can be assessed for conceptions after the first one with the birth of an affected child. 5. The probability of a child inheriting a disease from carrier parents is 25%.

Symptoms
Lethargy (worsens over time and can lead to coma),Life-threatening breathing difficulties, and weak muscle tone,Feeding difficulties,Abnormal muscle stiffness (spasticity),Profound intellectual disability and seizures
Conditions
Abnormally high levels of a molecule called glycine in the body (hyperglycinemia)
Drugs
Sodium benzoate and NMDA receptor agonists that include oral ketamine and dextromethorphan

Is there a cure/medications for nonketotic hyperglycinemia?

Nonketotic hyperglycinemia is an inborn metabolic disorder caused by the accumulation of glycine. Mutations in the genes GLDC and AMT that code for the enzymes involved in the breakdown of residual glycine are responsible for the disease. Glycine, an amino acid, is also a neurotransmitter that plays a role in the transmission of a signal from one neuron to another. Therefore, its accumulation has a severe adverse effect on the nervous system. In a few months after the birth, infants born with the error develop symptoms such as lethargy (which can lead to coma), life-threatening breathing difficulties, weak muscle tone, feeding difficulties, profound intellectual disability, abnormal muscle stiffness (spasticity), and seizures that are difficult to control.

Treatment/management
There is no method to reverse the cause of the disease. However, therapies are available to improve the phenotype.
The primary aim of treatments is to reduce glycine concentration in plasma. Therapy involves initiating with sodium benzoate and using NMDA receptor agonists that include oral ketamine and dextromethorphan to reduce glycemic stimulation.
After the establishment of the diagnosis, the following routine is important:
1. Developmental assessment
2. Orthopedic evaluation for scoliosis and hip dislocation, which is likely with age progression
3. Ophthalmic eval for the presence of cortical blindness
4. Cardiac evaluation to determine the therapy for pulmonary hypertension
5. Gastrointestinal referral to determine if enteral access is needed for nutrition.

Symptoms
Lethargy (worsens over time and can lead to coma),Life-threatening breathing difficulties, and weak muscle tone,Feeding difficulties,Abnormal muscle stiffness (spasticity),Profound intellectual disability and seizures
Conditions
Abnormally high levels of a molecule called glycine in the body (hyperglycinemia)
Drugs
Sodium benzoate and NMDA receptor agonists that include oral ketamine and dextromethorphan

Video related to nonketotic hyperglycinemia