Blue-cone monochromacy

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Blue cone monochromacy
Other namesX-linked achromatopsia
Specialty Ophthalmology
Symptoms poor ability or inability to distinguish colours, poor visual acuity, nystagmus, hemeralopia
Usual onsetcongenital
Differential diagnosis incomplete achromatopsia
Treatmentdark lenses
Frequency1 in 100,000

Blue cone monochromacy (BCM) is an inherited eye disease that causes severe color blindness, poor visual acuity, nystagmus and photophobia due to the absence of functional red (L) and green (M) cone photoreceptor cells in the retina. BCM is a recessive X-linked disease and almost exclusively affects XY karyotypes.

Contents

Cause

Cone cells are one kind of photoreceptor cell in the retina that are responsible for the photopic visual system and mediate color vision. The cones are categorized according to their spectral sensitivity:

MWS and LWS cones are most responsible for visual acuity as they are concentrated in the fovea centralis region of the retina, which constitutes the very center of the visual field. Blue cone monochromacy is a severe condition in which the cones sensitive to red or green light are missing or defective, and only S-cones sensitive to blue light and rods which are responsible for night (scotopic) vision are functional. [1] [2]

Symptoms

A variety of symptoms characterize BCM: [2] [3]

BCM symptoms are usually stationary, but some studies show evidence of disease progression. [4]

Poor Color Discrimination

The color vision of Blue cone monochromats is severely impaired. However, interaction of the blue cones and rod photoreceptors in mesopic vision (twilight) may enable some level of dichromacy. [5]

Genetics

Heredity

Because Blue cone monochromacy shares many symptoms with achromatopsia, it was historically treated as a subset of achromatopsia, called x-linked achromatopsia or atypical incomplete achromatopsia. Both of these names differentiated BCM specifically by how its inheritance pattern deviated from other forms of achromatopsia. While other forms (ACHM) follow autosomal inheritance, BCM is X-Linked. Once the molecular biological basis of BCM was understood, the more descriptive term Blue cone monochromacy became dominant in the literature.

Genes

The gene cluster responsible for BCM comprises 3 genes and is located at position Xq28, at the end of the q arm of the X chromosome. [6] The genes in the cluster are summarized in the following table:

Type OMIM Gene Locus Purpose
Locus Control Region 300824 LCR [1] Xq28Acts as a promoter of the expression of the two opsin genes thereafter, [1] and ensures that only one of the two opsins (LWS or MWS) is expressed exclusively in each cone. [7]
LWS opsin 300822 OPN1LW Xq28Encodes the LWS (red) photopsin protein.
MWS opsin 300821 OPN1MW Xq28Encodes the MWS (green) photopsin protein.

Originating from a recent duplication event, the two opsins are highly homologous (very similar), having only 19 dimorphic sites (amino acids that differ), [8] and are therefore 96% similar. [9] Furthermore, only 7 of these dimorphic sites lead to a functional difference between the genes, i.e. that tune the opsin's spectral sensitivity. In comparison, these opsin genes are only 40% homologous (similar) to OPN1SW (encoding the SWS photopsin and located on chromosome 7) and "RHO" (encoding rhodopsin, and located on chromosome 3). [9] OPN1SW and rhodopsin are unaffected in BCM.

Mutations

Since BCM is caused by non-functional M- and L-cones, it can result from the intersection of protanopia (no functional L-cones) and deuteranopia (no functional M-cones). Therefore the genetic causes of BCM include the genetic causes of protanopia and deuteranopia. These include (affecting either opsin gene): [9]

Data from the BCM International Patient Registry [12] shows that about 35% of Blue cone monochromacy stems from this 2-step process, where both genes are each affected by one of the above mutations. [9] The remaining 55% of Blue cone monochromats are caused by a deletion of the LCR. [9] In the absence of LCR, neither of the following two opsin genes are expressed.

Another disease of the retina that is associated with the position Xq28 is Bornholm Eye Disease (BED). [7] The point mutation W177R is a missense mutation that causes cone dystrophy when present on both opsin genes. [3]

Diagnosis

Children 2 months and older can be identified as possible Blue cone monochromats from observing an aversion to light and/or nystagmus, [13] but are not sufficient for diagnosis, and especially not the differential diagnosis with achromatopsia. The differential diagnosis can be achieved in a few ways:

Treatment

Corrective visual aides and personalized vision therapy provided by Low Vision Specialists may help patients correct glare and optimize their remaining visual acuity. Tinted lenses for photophobia allow for greater visual comfort. A magenta (mixture of red and blue) tint allows for best visual acuity since it protects the rods from saturation while allowing the blue cones to be maximally stimulated.

Gene therapy

There is no cure for Blue cone monochromacy. However, there are prospective gene therapy treatments which are currently being evaluated for safety and efficacy. Gene therapy is a general treatment for genetic disorders; it uses viral vectors to carry typical genes into cells (e.g. cone cells) that are not able to express functional genes (e.g. photopsins). It may be possible to restore color vision by adding missing opsin genes – or a functional copy of the entire gene complex – into the cone cells. In 2015, a team at the University of Pennsylvania evaluated possible outcome measures of BCM gene therapy. [17] Since 2011, several studies have performed gene therapy for BCM on mouse and rat models, [18] but there have been no clinical trials (on humans) and as of October 2022, none are publicly planned (according to ClinicalTrials.gov).[ citation needed ]

Epidemiology

BCM affects approximately 1/100,000 individuals. [14] The disease affects males much more than females due to its recessive X-linked nature, while females usually remain unaffected carriers of the BCM trait. [6]

History

Prior to the 1960s, Blue cone monochromacy was treated as a subset of achromatopsia. The first detailed description of achromatopsia was given in 1777, where the subject of the description:

...could never do more than guess the name of any color; yet he could distinguish white from black, or black from any light or bright color...He had 2 brothers in the same circumstances as to sight; and 2 brothers and sisters who, as well as his parents, had nothing of this defect.

— J. Huddart, "Article Title", An account of persons who could not distinguish colours (1777) [19]

In 1942, Sloan first distinguished typical and atypical achromatopsia, differentiated mainly on the inheritance patterns. [20] In 1953, Weale theorized that the atypical achromatopsia must stem from cone-monochromatism, but estimated a prevalence of only 1 in 100 million. [21] In the early 1960s, the inheritance of atypical achromatopsia led to a name change to x-linked achromatopsia, and at the same time, several studies demonstrated that Blue cone monochromats retain some Blue yellow color vision. [22] [23] A significant discovery was announced in 1989 (and 1993) by Nathans et al. [1] [2] who identified the genes which cause Blue cone monochromacy.

Related Research Articles

<span class="mw-page-title-main">Color blindness</span> Decreased ability to see color or color differences

Color blindness or color vision deficiency (CVD) is the decreased ability to see color or differences in color. The severity of color blindness ranges from mostly unnoticeable to full absence of color perception. Color blindness is usually an inherited problem or variation in the functionality of one or more of the three classes of cone cells in the retina, which mediate color vision. The most common form is caused by a genetic condition called congenital red–green color blindness, which affects up to 1 in 12 males (8%) and 1 in 200 females (0.5%). The condition is more prevalent in males, because the opsin genes responsible are located on the X chromosome. Rarer genetic conditions causing color blindness include congenital blue–yellow color blindness, blue cone monochromacy, and achromatopsia. Color blindness can also result from physical or chemical damage to the eye, the optic nerve, parts of the brain, or from medication toxicity. Color vision also naturally degrades in old age.

Achromatopsia, also known as Rod monochromacy, is a medical syndrome that exhibits symptoms relating to five conditions, most notably monochromacy. Historically, the name referred to monochromacy in general, but now typically refers only to an autosomal recessive congenital color vision condition. The term is also used to describe cerebral achromatopsia, though monochromacy is usually the only common symptom. The conditions include: monochromatic color blindness, poor visual acuity, and day-blindness. The syndrome is also present in an incomplete form that exhibits milder symptoms, including residual color vision. Achromatopsia is estimated to affect 1 in 30,000 live births worldwide.

<span class="mw-page-title-main">Retinitis pigmentosa</span> Gradual retinal degeneration leading to progressive sight loss

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. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Tetrachromacy</span> Type of color vision with four types of cone cells

Tetrachromacy is the condition of possessing four independent channels for conveying color information, or possessing four types of cone cell in the eye. Organisms with tetrachromacy are called tetrachromats.

<span class="mw-page-title-main">Cone cell</span> Photoreceptor cells responsible for color vision made to function in bright light

Cone cells or cones are photoreceptor cells in the retinas of vertebrates' eyes. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Cones function best in relatively bright light, called the photopic region, as opposed to rod cells, which work better in dim light, or the scotopic region. Cone cells are densely packed in the fovea centralis, a 0.3 mm diameter rod-free area with very thin, densely packed cones which quickly reduce in number towards the periphery of the retina. Conversely, they are absent from the optic disc, contributing to the blind spot. There are about six to seven million cones in a human eye, with the highest concentration being towards the macula.

<span class="mw-page-title-main">Monochromacy</span> Type of color vision

Monochromacy is the ability of organisms to perceive only light intensity without respect to spectral composition. Organisms with monochromacy lack color vision and can only see in shades of grey ranging from black to white. Organisms with monochromacy are called monochromats. Many mammals, such as cetaceans, the owl monkey and the Australian sea lion are monochromats. In humans, monochromacy is one among several other symptoms of severe inherited or acquired diseases, including achromatopsia or blue cone monochromacy, together affecting about 1 in 30,000 people.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

<span class="mw-page-title-main">Opsin</span> Class of light-sensitive proteins

Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become retinylidene proteins, but are usually still called opsins regardless. Most prominently, they are found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical signal, the first step in the visual transduction cascade. Another opsin found in the mammalian retina, melanopsin, is involved in circadian rhythms and pupillary reflex but not in vision. Humans have in total nine opsins. Beside vision and light perception, opsins may also sense temperature, sound, or chemicals.

<span class="mw-page-title-main">Duplex retina</span>

A duplex retina is a retina consisting of both rod cells and cone cells, which are the photoreceptor cells for two parallel but mostly separate visual systems. The rods enable the scotopic visual system, which is active in dim light. The cones enable the photopic visual system, which is active in bright light. While one is active, the other is generally inactive; either the rods are photobleached, or oversaturated, in bright light, or the cones are not sensitive enough to hyperpolarize, or instigate the phototrasduction cascade, in dim light. However, at mesopic (twilight) conditions, both visual systems are active. In this region of overlap, both systems are active and combine to contribute to mesopic vision.

Rhodopsin kinase is a serine/threonine-specific protein kinase involved in phototransduction. This enzyme catalyses the following chemical reaction:

<span class="mw-page-title-main">OPN1SW</span> Protein-coding gene in the species Homo sapiens

Blue-sensitive opsin is a protein that in humans is encoded by the OPN1SW gene.

<span class="mw-page-title-main">OPN1MW</span> Protein-coding gene in the species Homo sapiens

Green-sensitive opsin is a protein that in humans is encoded by the OPN1MW gene. OPN1MW2 is a similar opsin.

<span class="mw-page-title-main">OPN1LW</span> Protein-coding gene in humans

OPN1LW is a gene on the X chromosome that encodes for long wave sensitive (LWS) opsin, or red cone photopigment. It is responsible for perception of visible light in the yellow-green range on the visible spectrum. The gene contains 6 exons with variability that induces shifts in the spectral range. OPN1LW is subject to homologous recombination with OPN1MW, as the two have very similar sequences. These recombinations can lead to various vision problems, such as red-green colourblindness and blue monochromacy. The protein encoded is a G-protein coupled receptor with embedded 11-cis-retinal, whose light excitation causes a cis-trans conformational change that begins the process of chemical signalling to the brain.

<span class="mw-page-title-main">Cyclic nucleotide-gated channel alpha 3</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide-gated cation channel alpha-3 is a protein that in humans is encoded by the CNGA3 gene.

<span class="mw-page-title-main">Cyclic nucleotide gated channel beta 3</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide gated channel beta 3, also known as CNGB3, is a human gene encoding an ion channel protein.

<span class="mw-page-title-main">Evolution of color vision in primates</span> Loss and regain of colour vision during the evolution of primates

The evolution of color vision in primates is highly unusual compared to most eutherian mammals. A remote vertebrate ancestor of primates possessed tetrachromacy, but nocturnal, warm-blooded, mammalian ancestors lost two of four cones in the retina at the time of dinosaurs. Most teleost fish, reptiles and birds are therefore tetrachromatic while most mammals are strictly dichromats, the exceptions being some primates and marsupials, who are trichromats, and many marine mammals, who are monochromats.

Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

<span class="mw-page-title-main">Congenital red–green color blindness</span> Most common genetic condition leading to color blindness

Congenital red–green color blindness is an inherited condition that is the root cause of the majority of cases of color blindness. It has no significant symptoms aside from its minor to moderate effect on color vision. It is caused by variation in the functionality of the red and/or green opsin proteins, which are the photosensitive pigment in the cone cells of the retina, which mediate color vision. Males are more likely to inherit red–green color blindness than females, because the genes for the relevant opsins are on the X chromosome. Screening for congenital red–green color blindness is typically performed with the Ishihara or similar color vision test. There is no cure for color blindness.

References

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  17. ↑ Luo, X; Cideciyan, AV; Iannaccone, A; Roman, A J; Ditta, L C; Jennings, B J; Yatsenko, S; Sheplock, R; Sumaroka, A; Swider, M; Schwartz, S B; Wissinger, B; Kohl, S; Jacobson, S G (2015). "Blue cone monochromacy: visual function and efficacy outcome measures for clinical trials". PLOS ONE. 10 (4): e0125700. Bibcode:2015PLoSO..1025700L. doi: 10.1371/journal.pone.0125700 . PMC   4409040 . PMID   25909963.
  18. ↑ Zhang, Y; Deng, WT; Du, W; Zhu, P; Li, J; Xu, F; Sun, J; Gerstner, C D; Baehr, W; Boye Sanford, L; Zhao, C; Hauswirth, W W; Pang, J (2017). "Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy". Scientific Reports. 7 (6690): 6690. Bibcode:2017NatSR...7.6690Z. doi:10.1038/s41598-017-06982-7. PMC   5532293 . PMID   28751656.
  19. ↑ Huddart, J (1777). "An account of persons who could not distinguish colours". Philos. Trans. R. Soc. 67: 260. doi:10.1098/rstl.1777.0015. S2CID   186212155.
  20. ↑ Sloan, LL; Newhall, SM (1942). "Comparison of cases of atypical and typical achromatopsia". American Journal of Ophthalmology. 25 (8): 945–961. doi:10.1016/S0002-9394(42)90594-4.
  21. ↑ Weale, RA (1953). "Cone Monochromatism". The Journal of Physiology. 121 (3): 548–569. doi:10.1113/jphysiol.1953.sp004964. PMC   1366097 . PMID   13097391.
  22. ↑ Blackwell, H R; Blackwell, O M (1961). "Rod and cone receptor mechanisms in typical and atypical congenital achromatopsia". Vision Res. 1 (1–2): 62–107. doi:10.1016/0042-6989(61)90022-0.
  23. ↑ Spivey, B E (1965). "The X-linked recessive inheritance of atypical monochromatism". Arch. Ophthalmol. 74 (3): 327–333. doi:10.1001/archopht.1965.00970040329007. PMID   14338644.
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