Nonketotic Hyperglycinemia Overview - Nonketotic Hyperglycinemia

Disease Overview

Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a severe and rare disorder affecting about one in every 60,000 live births. The condition impairs nervous tissue, including the brain, leading to such symptoms as seizures, breathing and feeding difficulties, muscle limpness, and lethargy. Many patients progress to coma leading to death. Of those who survive, almost all patients go on to develop severe intellectual disability. The disease usually becomes apparent soon after birth, but sometimes symptoms start to arise in later infancy, or more rarely, in childhood or adulthood. It affects boys as often as girls, though girls tend to be more severely affected. Unfortunately, the condition is not currently curable, though treatments help limit the severity of certain symptoms. Through ongoing research, scientists hope to develop better treatments for this devastating disease.

The disorder is triggered by abnormally high amounts of a specific molecule, glycine. Glycine is a normal substance in the body, but at elevated levels it can cause significant medical problems. This molecule is an amino acid, one of the building blocks of proteins, the substances responsible for many body processes. In the brain and spinal cord glycine also acts a neurotransmitter, a signaling molecule that transmits messages between regions of the brain and nervous system. Under normal circumstances, excess glycine is broken down into its component parts by a group of proteins working together as an enzyme complex, called the “glycine cleavage system;” but in nonketotic hyperglycinemia (NKH) this system doesn’t work properly. Normally this enzyme complex is very active in the brain and liver, and lack of this functioning enzyme causes the clinical symptoms of NKH. Most patients with NKH have no detectable levels of the enzyme, but others do have some effective enzyme, just at much lower levels than normal. NKH is the second most common disorder of amino acid processing and metabolism (after phenylketonuria, or PKU.)

Most of the time, nonketotic hyperglycinemia (NKH) is caused by a mutation in one of two genes. These genes are portions of DNA, the heritable material passed down from parents to children. Both of these genes contribute to the formation of the glycine cleavage enzyme complex. Due to a mutation causing a change in the genetic sequence, the enzyme no longer works properly, leading to the buildup of glycine in the tissues. This excess glycine is thought to contribute to the clinical features of NKH, though researchers are still trying to understand the mechanisms involved.

nonketotic hyperglycinemia (NKH) is an autosomal recessive condition. That means that in order to get NKH, a person needs two copies of defective genes—one from each parent. People with a single defective gene do not have the disease, but if they have a child with another person with a defective gene, they have a one in four chance of having a child with the disorder. About 1 in 125 people are carriers of one of these defective genes.

Siblings of affected individuals are at risk for the disease. At conception, each sibling has a 25% chance of being affected. The sibling has a 50% chance of being unaffected but being a carrier for the mutated gene, and a 25% chance of being unaffected and not being a carrier for the gene. Once an at-risk sibling is known to be unaffected, his risk of being a carrier is 2/3. A sibling of a parent of a patient with the condition has a 50% chance of being a carrier as well. Carrier status can be tested with molecular genetic techniques.

There are several forms of nonketotic hyperglycinemia (NKH). In the most common kind, neonatal NKH, infants show problems in the first few hours or days of life. In infantile NKH, the next most common kind, symptoms begin later in infancy. Atypically, symptoms of the condition may appear later in childhood or even in adulthood.

Most of the time, nonketotic hyperglycinemia appears after a pregnancy that appeared normal. Sometimes a mother reports abnormal fetal movements, perceived as fetal “hiccoughs.”