The C2orf69 gene product is localized in the mitochondria, the powerhouse of the cell. Loss of C2orf69 leads to alteration of the energy production and sugar storage inside of the cell.
Suspected pathophysiologic mechanism
The loss of C2orf69, leads to reduction of complex I, II and V activity of the oxidative phosphorylation (OXPHOS). The OXPHOS is the main process in our cell to provide energy and converts mainly sugar to chemical energy (ATP) for cellular processes. This process is running in tiny specialized compartments in our cells, the so-called mitochondria. Moreover, C2orf69 loss compromise another energy metabolism pathway, as the activity of the glycogen-branching enzyme (GBE1) is reduced. Glycogen is a warehouse for storing sugar as long branched chains. If GBE1 is less active, the sugar chains have less branches and in line with this less branch tips. If energy is needed in the cells, the glycogen chains are spliced, beginning at the branch tips, into small sugar molecules, which can be used to generate energy in the mitochondria. However, if there are less branch tips available, less sugar molecules can be produced and therefore less energy is available in the cell. In conclusion the alteration of the OXPHOS process and the glycogen branching leading to a reduction of energy production in the cell and contribute on molecular level to the patients phenotype.
Type of mutations
All so far described patients harbour bi-allelic loss-of-function mutations in C2orf69. These loss-of-function mutations leading to incomplete translation of the genetic code of a gene to the protein. This truncated protein is either broken or instable and will be degraded. Hence, the function of the protein is missing in the cell. The disease has a so-called recessive inheritance, meaning, that both copies of a gene (allels) in our DNA, the maternal and the paternal, must be altered to develop the related disease.
Genetic testing
As the known pathogenic mutation distribute among the whole gene (c.280-c.847) sequencing of the whole gene will be necessary. This can be either achieved by panel-based, exome or genome sequencing. The gene consist only of 2 exons, therefor sanger sequencing might be also an option in clinical high suspicious cases. But as there is a strong overlap of the patient phenotype with other mitochondriopathies, an exome- or genome-wide approach will be most suitable for differential diagnosis.
Beside genetic testing, PAS (periodic acid–Schiff) staining of tissue sections might be helpful, as the glycogen deposits in the muscle and liver are a hallmark of the disease.