Glycine Encephalopathy (Nonketotic Hyperglycinemia) - Genetics


Glycine encephalopathy has an estimated incidence of 1 in 60,000, making it the second most common disorder of amino acid metabolism, after phenylketonuria. It is caused by a defect in the glycine cleavage system (GCS), which is made up of four protein subunits. Each of these four subunits is encoded by a separate gene. Defects in three of these four genes have been linked to glycine encephalopathy.

Gene Name Percent
GLDC encodes the "glycine dehydrogenase" subunit, also called "glycine decarboxylase" About 70-75% of cases of glycine encephalopathy result from mutations in the GLDC gene.
GCST or AMT encoding the "aminomethyltransferase" subunit About 20% of cases are caused by mutations in the AMT gene.
GCSH encoding the subunit "glycine cleavage system protein H" Mutations in the GCSH gene account for less than 1% of cases.

There is a fourth unit in the complex, dihydrolipoamide dehydrogenase or GCSL. However, to date there have been no mutations in GCSL found to be associated with glycine encephalopathy.

A small percentage of affected individuals do not have a detectable mutation in any of the three genes (listed above) but still have defective glycine-cleavage enzymatic activity. It is thought that these patients may have mutations in the genes encoding one of the cofactors associated with the GCS complex.

Defects in the GSC proteins can prevent the complex from functioning properly or can prevent the GCS complex from forming entirely. When the complex is unable to break down glycine properly, this causes excess glycine to build up to toxic levels in the body's organs and tissues. Damage caused by harmful levels of glycine in the brain and cerebrospinal fluid is responsible for the characteristic seizures, breathing difficulties, movement disorders, and mental retardation.

This disorder is inherited in an autosomal recessive pattern. The term "autosomal" signifies that the gene associated with the disorder is located on an autosome. In an autosomal recessive inheritance pattern, two defective copies of the gene (one inherited from each parent) are required in order for a child to be born with the disorder. Therefore, each parent of an individual with an autosomal recessive disorder has at least one defective copy of the gene. With autosomal recessive disorders, individuals with only one copy of a defective gene (heterozygotes) are considered "carriers" for the disorder. Carriers usually do not show signs or symptoms of the disorder.

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