GPT2 is a nuclear-encoded mitochondrial enzyme that catalyzes the reversible addition of an amino group from glutamate to pyruvate, thereby yielding alanine and alpha-ketoglutarate. In generating alpha-ketoglutarate, GPT2 plays a role in replenishing an intermediate of the tricarboxylic acid (TCA) cycle and mitochondrial metabolism. In catalyzing the conversion between glutamate and alanine, GPT2 is also involved in amino acid metabolism.
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. Mutations detected to date span the length of the gene and reflect inheritance of homozygous mutations – the same mutation on each allele – and compound heterozygous mutations – a different mutation on each allele (see below). Given its more recent discovery, the exact prevalence of GPT2-syndrome, as well as of mutant alleles present in a heterozygous state (i.e., unaffected carriers), 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 consanguineous marriage is more common.