Choroideremia
Encyclopedia
Choroideremia is an X-linked recessive
retinal degenerative disease that leads to the degeneration of the choriocapillaris
, the retinal pigment epithelium, and the photoreceptor of the eye.
Choroideremia (CHM) is a rare inherited disorder that causes progressive loss of vision due to degeneration of the choroid and retina. It occurs almost exclusively in males. In childhood, night blindness is the most common first symptom. As the disease progresses, there is loss of vision, frequently starting as an irregular ring that gradually expands both in toward central vision and out toward the extreme periphery.
Progression of the disease continues throughout the individual's life. Both the rate of change and the degree of visual loss are variable among those affected, even within the same family.
The actual vision loss is caused by degeneration of several layers of cells that are essential to sight. These layers, which line the inside of the back of the eye, are called the choroid, the retinal pigment epithelium (RPE), and the retina. The choroid is a network of blood vessels located between the retina and the sclera, the "white of the eye." Choroidal vessels provide oxygen and nutrients to both the RPE and the retina's photoreceptor cells.
The RPE, directly beneath the retina, supports the function of photoreceptor cells. Photoreceptors convert light into the electrical impulses that transfer messages to the brain where "seeing" actually occurs. In the early stages of Choroideremia, the choroid and the retinal pigment epithelium initially deteriorate. Eventually, photoreceptor cells also degenerate. As a result, vision is lost.
1 (REP1). Rab escort protein 2 (REP2) is 75% identical and can almost compensate for the loss of REP1. Though the eye does express the REP2 protein (no cell could survive without some REP activity) evidently, in the eye, this is not enough. The REPs are essential for the prenylation
of Rab
proteins. Studies have shown that there is a build up of unprenylated
Rab27
in lymphoblasts from Choroideremia patients. The link between the build up of unprenylated Rabs and blindness is not known.
, which begins in youth. As the disease progresses, a CHM sufferer loses their peripheral vision and depth perception, eventually losing all sight by middle age. In some cases, a severe loss of acuity and color perception become evident as the disease progresses.
The former Labour Member of Parliament
Siôn Simon
is a known sufferer.
The link between the loss of REP1 and the build up of unprenylated Rab27 and the degeneration of the eye is unknown as yet.
. Free genetic testing is available for US and Canadian Residents through the eyeGENE project which is coordinated by the National Eye Institute at the US National Institutes of Health. Preclinical trial work is underway at the Imperial College of London under the direction of Dr. Miguel Seabra and at Moorfields Eye Hospital in London under the direction of Dr. Robert MacLaren. In the United States preclinical trial work is underway at the University of Pennsylvania under the direction of Dr. Jean Bennett and Dr. Albert Maguire. Dr. Ian MacDonald is also pursuing clinical trials at the University of Alberta in Canada. The Choroideremia Research Foundation, an international non-profit organization that for over ten years has been dedicated to raising awareness and securing funding for choroideremia research, is currently funding pre-clinical trial work for Dr. Seabra and Dr. Bennett. Dr. Ian MacDonald also serves on the board of directors for the CRF and receives funding from CRF-Canada. Human clinical trials could start as early as 2012. CRF-Canada also supports Dr. Seabra's and Dr. MacLaren's work as does Fight for Sight.
In a procedure first attempted at Moorfields Hospital in London, researchers at the John Radcliffe Hospital
in Oxford
have used gene therapy to try and curtail the condition which is caused by a faulty gene labelled REP1
and causes the light sensitive cells in the eye to gradually die. The procedure will halt the cell death by introducing functioning copies of the gene into the eye.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
retinal degenerative disease that leads to the degeneration of the choriocapillaris
Choriocapillaris
The capillary lamina of choroid or choriocapillaris is a layer of capillaries that is immediately adjacent to Bruch's membrane in the choroid....
, the retinal pigment epithelium, and the photoreceptor of the eye.
Choroideremia (CHM) is a rare inherited disorder that causes progressive loss of vision due to degeneration of the choroid and retina. It occurs almost exclusively in males. In childhood, night blindness is the most common first symptom. As the disease progresses, there is loss of vision, frequently starting as an irregular ring that gradually expands both in toward central vision and out toward the extreme periphery.
Progression of the disease continues throughout the individual's life. Both the rate of change and the degree of visual loss are variable among those affected, even within the same family.
The actual vision loss is caused by degeneration of several layers of cells that are essential to sight. These layers, which line the inside of the back of the eye, are called the choroid, the retinal pigment epithelium (RPE), and the retina. The choroid is a network of blood vessels located between the retina and the sclera, the "white of the eye." Choroidal vessels provide oxygen and nutrients to both the RPE and the retina's photoreceptor cells.
The RPE, directly beneath the retina, supports the function of photoreceptor cells. Photoreceptors convert light into the electrical impulses that transfer messages to the brain where "seeing" actually occurs. In the early stages of Choroideremia, the choroid and the retinal pigment epithelium initially deteriorate. Eventually, photoreceptor cells also degenerate. As a result, vision is lost.
Pathophysiology
Choroideremia is caused by the deletion of the Rab escort proteinRab escort protein
Rab escort protein 1 also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.- Function :This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme...
1 (REP1). Rab escort protein 2 (REP2) is 75% identical and can almost compensate for the loss of REP1. Though the eye does express the REP2 protein (no cell could survive without some REP activity) evidently, in the eye, this is not enough. The REPs are essential for the prenylation
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
of Rab
Rab (G-protein)
The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane...
proteins. Studies have shown that there is a build up of unprenylated
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
Rab27
Rab27
Rab27 is a member of the Rab subfamily of GTPases. Rab27 is post translationally modified by the addition of two geranylgeranyl groups on the two C-terminal cysteines.-Pathology:...
in lymphoblasts from Choroideremia patients. The link between the build up of unprenylated Rabs and blindness is not known.
Presentation
Generally, only men show symptoms of this disease, although in rare cases some women also acquire it. Initially a person suffering from choroideremia has night blindnessNyctalopia
Nyctalopia 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...
, which begins in youth. As the disease progresses, a CHM sufferer loses their peripheral vision and depth perception, eventually losing all sight by middle age. In some cases, a severe loss of acuity and color perception become evident as the disease progresses.
The former Labour Member of Parliament
Member of Parliament
A Member of Parliament is a representative of the voters to a :parliament. In many countries with bicameral parliaments, the term applies specifically to members of the lower house, as upper houses often have a different title, such as senate, and thus also have different titles for its members,...
Siôn Simon
Siôn Simon
Siôn Llewelyn Simon is a British Labour politician, who served as the Member of Parliament for Birmingham Erdington from 2001 to 2010. Simon was the Parliamentary Under-Secretary of State for Creative Industries...
is a known sufferer.
The link between the loss of REP1 and the build up of unprenylated Rab27 and the degeneration of the eye is unknown as yet.
Prognosis
There is a genetic blood test to diagnose Choroideremia. It was created by Dr. Ian MacDonald at the University of AlbertaUniversity of Alberta
The University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
. Free genetic testing is available for US and Canadian Residents through the eyeGENE project which is coordinated by the National Eye Institute at the US National Institutes of Health. Preclinical trial work is underway at the Imperial College of London under the direction of Dr. Miguel Seabra and at Moorfields Eye Hospital in London under the direction of Dr. Robert MacLaren. In the United States preclinical trial work is underway at the University of Pennsylvania under the direction of Dr. Jean Bennett and Dr. Albert Maguire. Dr. Ian MacDonald is also pursuing clinical trials at the University of Alberta in Canada. The Choroideremia Research Foundation, an international non-profit organization that for over ten years has been dedicated to raising awareness and securing funding for choroideremia research, is currently funding pre-clinical trial work for Dr. Seabra and Dr. Bennett. Dr. Ian MacDonald also serves on the board of directors for the CRF and receives funding from CRF-Canada. Human clinical trials could start as early as 2012. CRF-Canada also supports Dr. Seabra's and Dr. MacLaren's work as does Fight for Sight.
In a procedure first attempted at Moorfields Hospital in London, researchers at the John Radcliffe Hospital
John Radcliffe Hospital
The John Radcliffe Hospital is a large tertiary teaching hospital in Oxford, England.It is the main teaching hospital for Oxford University and Oxford Brookes University. As such, it is a well-developed centre of medical research. It also incorporates the Medical School of the University of Oxford....
in Oxford
Oxford
The city of Oxford is the county town of Oxfordshire, England. The city, made prominent by its medieval university, has a population of just under 165,000, with 153,900 living within the district boundary. It lies about 50 miles north-west of London. The rivers Cherwell and Thames run through...
have used gene therapy to try and curtail the condition which is caused by a faulty gene labelled REP1
Rab escort protein
Rab escort protein 1 also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.- Function :This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme...
and causes the light sensitive cells in the eye to gradually die. The procedure will halt the cell death by introducing functioning copies of the gene into the eye.