Choroideremia (; CHM) is a rare, X-linked recessive form of hereditary

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which the ...

l degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood

night blindness Nyctalopia (; ), also called night-blindness, is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition ...

, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's 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 In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

mutation in the ''CHM''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

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 The choroid, also known as the choroidea or choroid coat, is a part of the uvea, the vascular layer of the eye, and contains connective tissues, and lies between the retina and the sclera. The human choroid is thickest at the far extreme rea ...

. As of 2019, there is no treatment for choroideremia; however,

retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use reti ...

gene therapy Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...

clinical trials have demonstrated a possible treatment.

Presentation

Since the ''CHM'' gene is located on the

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...

, 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. The first symptom many individuals with choroideremia notice is a significant loss of night vision, which begins in youth. Peripheral vision loss occurs gradually, starting as a ring of vision loss, and continuing on to "tunnel vision" in adulthood. Individuals with choroideremia tend to maintain good

visual acuity Visual acuity (VA) commonly refers to the clarity of vision, but technically rates an examinee's ability to recognize small details with precision. Visual acuity is dependent on optical and neural factors, i.e. (1) the sharpness of the retinal ...

into their 40s, but eventually lose all sight at some point in the 50–70 age range. A study of 115 individuals with choroideremia found that 84% of patients under the age of 60 had a visual acuity of 20/40 or better, while 33% of patients over 60 years old had a visual acuity of 20/200 or worse. The most severe visual acuity impairment (only being able to count fingers or worse) did not occur until the seventh decade of life. The same study found the mean rate of visual acuity loss to be about 0.09 logMAR per 5 years, which is roughly 1 row on a Snellen chart.

Diagnosis

A diagnosis of choroideremia can be made based on family history, symptoms and the characteristic appearance of the fundus. However, choroideremia shares several clinical features with

retinitis pigmentosa Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field). As peripheral vision worsens, people may ...

, a similar but broader group of retinal degenerative diseases, making a specific diagnosis difficult without genetic testing. Because of this choroideremia is often initially misdiagnosed as retinitis pigmentosa. A variety of different

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

techniques can be used to make a differential diagnosis.

Management

While nothing currently can be done to stop or reverse the retinal degeneration, there are steps that can be taken to slow the rate of vision loss. UV-blocking sunglasses for outdoors, appropriate dietary intake of fresh fruit and leafy green vegetables, antioxidant vitamin supplements, and regular intake of dietary omega-3 very-long-chain fatty acids are all recommended. One study found that a dietary supplement of

lutein Lutein (;"Lutein"

increases macular pigment levels in patients with choroideremia. Over a long period of time, these elevated levels of pigmentation "could" slow retinal degeneration. Additional interventions that may be needed include surgical correction of retinal detachment and cataracts, low vision services, and counseling to help cope with depression, loss of independence, and anxiety over job loss.

Gene therapy

Gene therapy is currently not a treatment option, however human

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dieta ...

for both choroideremia and Leber's congenital amaurosis (LCA) have produced somewhat promising results.Pallab Ghosh, 2011, "Health: Gene therapy used in a bid to save a man's sight," at ''BBC News'' (online), October 27, 2011, se

accessed 23 April 2015. Clinical trials of gene therapy for patients with LCA began in 2008 at three different sites. In general, these studies found the therapy to be safe, somewhat effective, and promising as a future treatment for similar retinal diseases. In 2011, the first gene therapy treatment for choroideremia was administered. The surgery was performed by

Robert MacLaren Robert E. MacLaren FMedSci FRCOphth FRCS FACS VR (born 14 November 1966) is a British ophthalmologist who has led pioneering work in the treatment of blindness caused by diseases of the retina. He is Professor of Ophthalmology at the Unive ...

, Professor of Ophthalmology at the University of Oxford and leader of the Clinical Ophthalmology Research Group at the Nuffield Laboratory of Ophthalmology (NLO).Abigail Beall, 2014, "Gene therapy restores sight in people with eye disease," ''New Scientist'' (online), January 16, 2014, se

accessed 23 April 2015. In the study, 2 doses of the adeno associated virus, AAV.REP1 vector were injected subretinally in 12 patients with choroideremia. There study had 2 objectives: * to assess the safety and tolerability of the AAV.REP1 vector * to observe the therapeutic benefit, or slowing of the retinal degeneration, of the gene therapy during the study and at a 24-month post-treatment time point Despite retinal detachment caused by the injection, the study observed initial improved rod and cone function, warranting further study. In 2016, researchers were optimistic that the positive results of 32 choroideremia patients treated over four and a half years with gene therapy in four countries could be long-lasting.

Preimplantation genetic diagnosis

For women who carry a mutation in the CHM gene, preimplantation genetic diagnosis can be used during the

in-vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) ...

process to select unaffected embryos to implant. This process call be applied to any monogenic disease.

Other potential therapies

While choroideremia is an ideal candidate for gene therapy there are other potential therapies that could restore vision after it has been lost later in life. Foremost of these is

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...

therapy A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many differe ...

. A clinical trial published in 2014 found that a subretinal injection of human embryonic stem cells in patients with

age-related macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

and

Stargardt disease Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants ( ...

was safe and improved vision in most patients. Out of 18 patients, vision improved in 10, improved or remained the same in 7, and decreased in 1 patient, while no improvement was seen in the untreated eyes. The study found "no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue." A 2015 study used

CRISPR/Cas9 Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic ...

to repair mutations in patient-derived induced pluripotent stem cells that cause X-linked retinitis pigmentosa. This study suggests that a patient's own repaired cells could be used for therapy, reducing the risk of immune rejection and

ethical issues Ethics or moral philosophy is a branch of philosophy that "involves systematizing, defending, and recommending concepts of right and wrong behavior".''Internet Encyclopedia of Philosophy'' The field of ethics, along with aesthetics, concerns m ...

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 Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar ...

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 In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

prenyl Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar ...

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 In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

abnormalities in

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...

). REP2, a protein that is 75% identical and 90% similar to REP1, is able to significantly compensate for the loss of REP1 outside the eye. It is thought that REP2 is not able to fully compensate for the loss of REP1 in the retina.

RAB27A Ras-related protein Rab-27A is a protein that in humans is encoded by the ''RAB27A'' gene. Function The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in pr ...

, a Rab that has essential functions in the retina, has been shown to be preferentially prenylated by REP1. Additionally, the Rab27a-REP1 and Rab27a-REP2 complexes have different

affinities In post-classical history, an affinity was a collective name for the group (retinue) of (usually) men whom a lord gathered around himself in his service; it has been described by one modern historian as "the servants, retainers, and other fol ...

for the Rab geranylgeranyltransferase enzyme, possibly explaining REP2's inability to fully compensate for REP1 in the retina.

Culture

A number of individuals in public roles are living with choroidermia, and some have been involved in fundraising efforts for the disease. The former

UK Labour The Labour Party is a political party in the United Kingdom that has been described as an alliance of social democrats, democratic socialists and trade unionists. The Labour Party sits on the centre-left of the political spectrum. In all gene ...

Member of Parliament A member of parliament (MP) is the representative in parliament of the people who live in their electoral district. In many countries with bicameral parliaments, this term refers only to members of the lower house since upper house members o ...

Siôn Simon is a known to have the condition. Comic and activist E.J. Scott, partner of ''

Daredevil Daredevil may refer to: * A stunt performer Arts and media Comics * Daredevil (Lev Gleason Publications), a fictional 1940s superhero popularized by writer-artist Charles Biro * Daredevil (Marvel Comics character), a Marvel comic book superhero ...

'' actress Deborah Ann Woll, also has choroideremia, and is involved in regular fundraising efforts.E.J. Scott, 2015, "This is my 40: Running 7 continents in 1 year, blindfolded," at ''Crowdrise'' (online crowdsourcing), undated, se

accessed 23 April 2015.

References

External links

Genetic testing for Choroideremia.

Choroideremia Research Foundation is an international not-for-profit organization dedicated to supporting the Choroideremia community
{{Inherited disorders of trafficking Genetic diseases and disorders Disorders of choroid and retina