GPT2 is a protein encoded by genes located in the nucleus of cells but that localizes to cellular organelles termed mitochondria – the energy production centers of cells. GPT2 is an enzyme that catalyzes (speeds up) a cellular biochemical reaction involved in mitochondrial metabolism. This reaction also plays a role in the metabolism of amino acids – the components of proteins.
Clinical characterizations of patients with disease-causing mutations in GPT2 have only more recently been reported and the available reports are relatively few. Identification of a common set of features reflective of a syndrome resulting from loss-of-function or deleterious mutations in GPT2 is, thus, a more recent discovery. Based on the reported clinical phenotypes, GPT2-syndrome is a neurological syndrome with core features including intellectual disability; reduced brain growth; developmental delay, as well as regression of achieved milestones (e.g., walking); progressive motor symptoms, which may lead to spastic paraplegia; and seizures.
The GPT2-syndrome is inherited in an autosomal recessive manner, which means that each copy of the GPT2 gene (one from the mother and one from the father) needs to contain a mutation abolishing the protein’s function in order for an individual to be affected. If an individual contains one mutant GPT2 gene and one normal GPT2 gene, this individual is considered a “carrier” of a GPT2 mutation. Mutations detected to date span the length of the gene and reflect inheritance of homozygous mutations – the same mutation on each copy of the GPT2 gene – and compound heterozygous mutations – a different mutation on each copy of the GPT2 gene (see below). Given its more recent discovery, the exact prevalence of GPT2-syndrome is at present unclear. However, estimates based on analysis of a dataset derived from a public database of unrelated individuals sequenced as part of various disease-specific and population genetic studies (i.e., the Exome Aggregation Consortium, ExAC, database) suggest that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2. This would lead to an estimated prevalence, with respect to GPT2-syndrome resulting from deleterious homozygous or compound heterozygous mutations in GPT2, of 1 in 246,016 individuals. Note, prevalence of GPT2-syndrome may be greater in some populations such as those in which marriage between closely related individuals is more common.