Hyperglycinemia nonketotic; Glycine encephalopathy (Glycine encephalopathy) - Genes and GLDC AMT.
Glycine encephalopathy, also called nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high concentrations of glycine. Glycine acts as a neurotransmitter. This disease is caused by a deficiency of an enzyme that breaks glycine in the body, leading to accumulation of excess glycine in tissues and organs, especially the brain, causing serious medical problems.
The most common form of glycine encephalopathy, classical type, manifests shortly after birth. Affected children have lethargy, feeding difficulties, hypotonia, spastic movement disorders and respiratory problems that threaten life. Most children who survive these early signs and symptoms develop profound intellectual disability and seizures that are difficult to treat. For unknown reasons, affected males are more likely to survive and have less severe developmental problems that affected women.
They described other types of glycine encephalopathy with signs and symptoms variables. The most common of these atypical types is the infantile form. Children with this type of glycine encephalopathy develop normally until 6 months of age, but thereafter manifest developmental delay and may start having seizures. As they grow older, many manifest intellectual disabilities, abnormal movements and behavioral problems. Other atypical types of glycine encephalopathy appear later in childhood or adulthood and lead to a variety of medical problems that mainly affect the nervous system.
Rarely, the characteristic features of classical glycine encephalopathy improve with time. These cases are classified as transient glycine encephalopathy. In this form of the disease, elevated concentrations of glycine at birth decrease normal or near normal levels. However, even after glycine concentrations diminish some individuals exhibit mental retardation and seizures.
In about 80% of cases, the disease is due to mutations in the gene GLDC. Between 10% and 15% of the remaining cases the disease is due to changes in the AMT gene. In a small percentage of those affected, the cause of this disease is unknown. These genes encode proteins that act together as part of an enzyme complex responsible for breaking down into smaller pieces glycine.
The AMT gene, located on the short arm of chromosome 3 (3p21.31), and GLDC gene, located on the short arm of chromosome 9 (9p22), encoding enzymes and dehydrogenase aminomethyltransferase respectively glycine. Each of these enzymes corresponds to one of the four subunits that make up the complex glycine cleavage. Inside the cells, the complex is active in mitochondria. As the name suggests, the glycine cleavage enzyme processes glycine breaking it down into smaller fragments. Glycine is an amino acid which also acts as a neurotransmitter. The breakdown of excess glycine is necessary for normal development and function of nerve cells in the brain and spinal cord.
They have identified more than a dozen gene mutations in the AMT and more than 40 mutations in the GLDC gene in affected individuals. Most of these genetic changes alter the amino acids in the aminomethyltransferase and glycine dehydrogenase. The most frequent mutation in the gene GLDC changes the amino acid serine to isoleucine at amino acid position 564 in the enzyme (Ser564Ile or S564I). Other mutations eliminate genetic material of AMT and GLDC gene, or disrupt how genetic information of the gene is expressed to encode the enzymes. Mutations in any of these genes prevent the complex decomposes glycine correctly, which can lead to accumulation of glycine to toxic concentrations in the organs and tissues. Damage from harmful amounts of this molecule in the brain and spinal cord are responsible for mental retardation, seizures , and respiratory difficulties characteristics of glycine encephalopathy.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with glycine encephalopathy, by complete PCR amplification of the exons of the AMT and GLDC genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).