Choroideremia (; CHM) is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individuals life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.Choroideremia is caused by a loss-of-function mutation in the CHM gene which encodes Rab escort protein 1 (REP1), a protein involved in lipid modification of Rab proteins. While the complete mechanism of disease is not fully understood, the lack of a functional protein in the retina results in cell death and the gradual deterioration of the retinal pigment epithelium (RPE), photoreceptors and the choroid.As of 2019, there is no treatment for choroideremia; however, retinal gene therapy clinical trials have demonstrated a possible treatment. Presentation
Since the CHM gene is located on the X chromosome, symptoms are seen almost exclusively in men. While there are a few exceptions, female carriers have a noticeable lack of pigmentation in the RPE but do not experience any symptoms. Female carriers have a 50% chance of having either an affected son or a carrier daughter, while a male with choroideremia will have all carrier daughters and unaffected sons. Even though the disease progression can vary significantly, there are general trends.
A 2015 study used CRISPR/Cas9 to repair mutations in patient-derived induced pluripotent stem cells that cause X-linked retinitis pigmentosa. This study suggests that a patients own repaired cells could be used for therapy, reducing the risk of immune rejection and ethical issues that come with the use of embryonic stem cells. Research
History
Choroideremia was first described in 1872 by an Austrian ophthalmologist, Ludwig Mauthner. Initially, the condition was thought to be a developmental disorder which caused the absence of a majority of the choroid (hence the probable use of the ancient Greek suffix “eremia,” meaning barren land or desert). After several decades, the non-progressive nature of the disease was called into doubt, eventually being rejected by Paymerer et al. in 1960. The CHM gene was identified and cloned in 1990 by Frans P.M. Cremers. Basic research
In many inherited retinal diseases the protein affected by the mutation is directly involved in the light sensing function of the eye, however this is not the case in choroideremia. REP1 assists the prenylation of Rab G-proteins by binding and presenting them to the Rab geranylgeranyltransferase subunit. REP1 also escorts prenylated Rabs through the cytoplasm by binding the hydrophobic prenyl groups and carrying them to a specific destination membrane.In healthy individuals, REP1 is found throughout all of the cells of the body, however patients with choroideremia only experience vision loss, and not broader, systemic symptoms (with the exception of a study that found crystals and fatty acid abnormalities in leukocytes).