Gordon Holmes syndrome is a rare condition. Its prevalence is unknown.

Gordon Holmes syndrome can be caused by mutations in the RNF216 or PNPLA6 gene. Some people with the condition do not have mutations in these genes, indicating that mutations in other genes are likely involved in the condition.

The protein produced from the RNF216 gene is involved in a cellular process, called ubiquitination, by which unneeded proteins are tagged with a molecule called ubiquitin. The ubiquitin tag signals for the protein to be broken down. One of several proteins tagged by RNF216 is a protein found in nerve cells (neurons) that plays a role in a process called synaptic plasticity. Synaptic plasticity is the ability of the connections between neurons (synapses) to change and adapt over time in response to experience. This process is critical for learning and memory.

RNF216 gene mutations impair the ability of the RNF216 protein to tag unneeded proteins to be broken down. Impaired breakdown of the neuronal protein disrupts normal synaptic connections and plasticity, which likely contributes to dementia in people with Gordon Holmes syndrome. It is unclear how a lack of RNF216 protein function causes hypogonadotropic hypogonadism or cerebellar ataxia.

The PNPLA6 gene provides instructions for making a protein called neuropathy target esterase (NTE), which helps regulate the amount of certain fats (lipids) that make up the outer membrane surrounding cells. The correct levels of these lipids are critical to the stability and function of cell membranes. NTE is found most abundantly in the nervous system and is thought to help maintain the stability of membranes surrounding neurons. NTE is also thought to play a role in the release of hormones from the pituitary gland, a process that requires particular changes in the cell membrane. The pituitary gland is located at the base of the brain and produces several hormones, including those that help direct sexual development and growth.

PNPLA6 gene mutations are thought to impair NTE's function. Researchers speculate that such an impairment alters the balance of lipids in the cell membrane. This imbalance may damage neurons in the brain, causing cerebellar ataxia, and impair the pituitary gland's release of hormones involved in sexual development, leading to hypogonadotropic hypogonadism. Individuals with Gordon Holmes syndrome caused by PNPLA6 gene mutations do not appear to develop dementia.