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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.


Signs and symptoms

The five symptoms associated with achromatopsia are: #
Color blindness Color blindness or color vision deficiency (CVD) is the decreased ability to see color or differences in color. It can impair tasks such as selecting ripe fruit, choosing clothing, and reading traffic lights. Color blindness may make some aca ...
- usually monochromacy # Reduced
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 ...
- uncorrectable with lenses # Hemeralopia – with the subject exhibiting
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
# Nystagmus # Iris operating abnormalities The syndrome is typically first noticed in children around six months of age due to their
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
or their nystagmus. The nystagmus becomes less noticeable with age but the other symptoms of the syndrome become more relevant as school age approaches. Visual acuity and stability of the eye motions generally improve during the first six to seven years of life – but remain near 20/200. Otherwise the syndrome is considered stationary and does not worsen with age. If the light level during testing is optimized, achromats may achieve corrected visual acuity of 20/100 to 20/150 at lower light levels, regardless of the absence of color. The
fundus ''Fundus'' (Latin for "bottom") is an anatomical term referring to that part of a concavity in any organ, which is at the far end from its opening. It may refer to: Anatomy * Fundus (brain), the deepest part of any sulcus of the cerebral cortex * ...
of the eye appears completely normal. Achromatopsia can be classified as ''complete'' or ''incomplete''. In general, symptoms of incomplete achromatopsia are attenuated versions of those of complete achromatopsia. Individuals with incomplete achromatopsia have reduced visual acuity with or without nystagmus or photophobia. Incomplete achromats show only partial impairment of cone cell function.


Cause

Achromatopsia is sometimes called rod monochromacy (as opposed to blue cone monochromacy), as achromats exhibit a complete absence of
cone cell Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Con ...
activity via electroretinography in photopic lighting. There are at least four genetic causes of achromatopsia, two of which involve cyclic nucleotide-gated ion channels ( ACHM2, ACHM3), a third involves the cone photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown. Known genetic causes of this include mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2) and CNGB3 (ACHM3), the cone cell
transducin Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors. L ...
, GNAT2 (ACHM4), subunits of cone
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many o ...
PDE6C (ACHM5, OMIM 613093) and
PDEH The enzyme phorbol-diester hydrolase (EC 3.1.1.51) catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain uncha ...
(ACHM6, OMIM 610024), and ATF6 (ACHM7, OMIM 616517).


Pathophysiology

The hemeralopic aspect of achromatopsia can be diagnosed non-invasively using electroretinography. The response at low ( scotopic) and median ( mesopic) light levels will be normal but the response under high light level ( photopic) conditions will be absent. The mesopic level is approximately a hundred times lower than the clinical level used for the typical high level electroretinogram. When as described; the condition is due to a saturation in the neural portion of the retina and not due to the absence of the photoreceptors per se. In general, the molecular pathomechanism of achromatopsia is either the inability to properly control or respond to altered levels of
cGMP CGMP is an initialism. It can refer to: *cyclic guanosine monophosphate (cGMP) *current good manufacturing practice (cGMP) *CGMP, Cisco Group Management Protocol, the Cisco version of Internet Group Management Protocol The Internet Group Managem ...
; particularly important in
visual perception Visual perception is the ability to interpret the surrounding environment through photopic vision (daytime vision), color vision, scotopic vision (night vision), and mesopic vision (twilight vision), using light in the visible spectrum refl ...
as its level controls the opening of cyclic nucleotide-gated ion channels (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization and cessation of
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
release Release may refer to: * Art release, the public distribution of an artistic production, such as a film, album, or song * Legal release, a legal instrument * News release, a communication directed at the news media * Release (ISUP), a code to id ...
. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in
cone cell Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Con ...
s. When expressed alone, CNGB3 cannot produce functional channels, whereas this is not the case for CNGA3. Coassembly of CNGA3 and CNGB3 produces channels with altered membrane expression, ion permeability ( Na+ vs. K+ and Ca2+), relative efficacy of cAMP/cGMP activation, decreased outward
rectification Rectification has the following technical meanings: Mathematics * Rectification (geometry), truncating a polytope by marking the midpoints of all its edges, and cutting off its vertices at those points * Rectifiable curve, in mathematics * Recti ...
, current flickering, and sensitivity to block by L-cis-diltiazem. Mutations tend to result in the loss of CNGB3 function or gain of function—often increased affinity for cGMP—of CNGA3. cGMP levels are controlled by the activity of the
cone cell Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Con ...
transducin Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors. L ...
, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels by
photon A photon () is an elementary particle that is a quantum of the electromagnetic field, including electromagnetic radiation such as light and radio waves, and the force carrier for the electromagnetic force. Photons are Massless particle, massless ...
s. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...
. Molecular diagnosis can be established by identification of biallelic variants in the causative genes. Molecular genetic testing approaches used in achromatopsia can include targeted analysis for the common CNGB3 variant c.1148delC (p.Thr383IlefsTer13), use of a multigenerational panel, or comprehensive genomic testing.


ACHM2

While some mutations in CNGA3 result in truncated and, presumably, non-functional channels this is largely not the case. While few mutations have received in-depth study, at least one mutation does result in functional channels. Curiously, this mutation, T369S, produces profound alterations when expressed without CNGB3. One such alteration is decreased affinity for Cyclic guanosine monophosphate. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increased
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
permeability. When mutant T369S channels coassemble with CNGB3, however, the only remaining aberration is increased calcium permeability. While it is not immediately clear how this increase in Ca2+ leads to achromatopsia, one hypothesis is that this increased current decreases the signal-to-noise ratio. Other characterized mutations, such as Y181C and the other S1 region mutations, result in decreased current density due to an inability of the channel to traffic to the surface. Such loss of function will undoubtedly negate the
cone cell Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Con ...
's ability to respond to visual input and produce achromatopsia. At least one other missense mutation outside of the S1 region, T224R, also leads to loss of function.


ACHM3

While very few mutations in CNGB3 have been characterized, the vast majority of them result in truncated channels that are presumably non-functional. This will largely result in
haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
, though in some cases the truncated proteins may be able to coassemble with wild-type channels in a dominant negative fashion. The most prevalent ACHM3 mutation, T383IfsX12, results in a non-functional truncated protein that does not properly traffic to the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
. The three missense mutations that have received further study show a number of aberrant properties, with one underlying theme. The R403Q mutation, which lies in the pore region of the channel, results in an increase in outward current rectification, versus the largely linear current-voltage relationship of wild-type channels, concomitant with an increase in cGMP affinity. The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP. It is the increased affinity for cGMP and cAMP in these mutants that is likely the disorder-causing change. Such increased affinity will result in channels that are insensitive to the slight concentration changes of cGMP due to light input into the retina.


ACHM4

Upon activation by light, cone opsin causes the exchange of GDP for GTP in the guanine nucleotide binding protein (
G-protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...
) α-
transducin Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors. L ...
g activity polypeptide 2 (GNAT2). This causes the release of the activated α-subunit from the inhibitory β/γ-subunits. This α-subunit then activates a
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many o ...
that catalyzes the conversion of cGMP to GMP, thereby reducing current through CNG3 channels. As this process is absolutely vital for proper color processing it is not surprising that mutations in GNAT2 lead to achromatopsia. The known mutations in this gene, all result in truncated proteins. Presumably, then, these proteins are non-functional and, consequently, cone opsin that has been activated by light does not lead to altered cGMP levels or photoreceptor membrane hyperpolarization.


Management


Gene therapy

As achromatopsia is linked to only a few single-gene mutations, it is a good candidate for gene therapy.
Gene therapy Gene therapy is a 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 human D ...
is a technique for injecting functional genes into the cells that need them, replacing or overruling the original alleles linked to achromatopsia, thereby curing it - at least in part. Achromatopsia has been a focus of gene therapy since 2010, when achromatopsia in dogs was partially cured. Several clinical trials on humans are ongoing with mixed results.


Eyeborg

Since 2003, a cybernetic device called the eyeborg has allowed people to perceive color through sound waves. This form of Sensory substitution maps the hue perceived by a camera worn on the head to a pitch experienced through bone conduction according to a sonochromatic scale. This allows achromats (or even the totally blind) to perceive - or estimate - the color of an object. Achromat and artist Neil Harbisson was the first to use the eyeborg in early 2004, which allowed him to start painting in color. He has since acted as a spokesperson for the technology, namely in
2012 TED Talk
A 2015 study suggests that achromats who use the Eyeborg for several years exhibit neural plasticity, which indicates the sensory substitution has become intuitive for them.


Other accommodations

While gene therapy and the Eyeborg may currently have low uptake with achromats, there are several more practical ways for achromats to manage their condition: * Some colors can be estimated through the use of colored filters. By comparing the luminosity of a color with and without a filter (or between two different filters), the color can be estimated. This is the premise of monocular lenses and the SeeKey. In some US states, achromats can use a red filter while driving to determine the color of a traffic light. * To alleviate photophobia stemming from hemeralopia, dark red or plum colored filters as either sunglasses or tinted contacts are very helpful at decreasing light sensitivity. * To manage the low visual acuity that is typical of achromatopsia, achromats may use telescopic systems, specifically when driving, to increase the resolution of an object of interest.


Epidemiology

Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people. However, on the small
Micronesia Micronesia (, ) is a subregion of Oceania, consisting of about 2,000 small islands in the western Pacific Ocean. It has a close shared cultural history with three other island regions: the Philippines to the west, Polynesia to the east, and ...
n atoll of Pingelap, approximately five percent of the atoll's 3,000 inhabitants are affected. This is the result of a
population bottleneck A population bottleneck or genetic bottleneck is a sharp reduction in the size of a population Population typically refers to the number of people in a single area, whether it be a city or town, region, country, continent, or the world. Go ...
caused by a typhoon and ensuing famine in the 1770s, which killed all but about twenty islanders, including one who was heterozygous for achromatopsia. The people of this region have termed achromatopsia "maskun", which literally means "not see" in Pingelapese. This unusual population drew neurologist Oliver Sacks to the island for which he wrote his 1997 book, '' The Island of the Colorblind''.


Blue cone monochromacy

Blue cone monochromacy (BCM) is another genetic condition causing monochromacy. It mimics many of the symptoms of incomplete achromatopsia and before the discovery of its molecular biological basis was commonly referred to as ''x-linked achromatopsia'', ''sex-linked achromatopsia'' or ''atypical achromatopsia''. BCM stems from mutations or deletions of the OPN1LW and OPN1MW genes, both 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 se ...
. As a recessive x-linked condition, BCM disproportionately affects males, unlike typical achromatopsia.


Cerebral achromatopsia

Cerebral achromatopsia]is a form of acquired
color blindness Color blindness or color vision deficiency (CVD) is the decreased ability to see color or differences in color. It can impair tasks such as selecting ripe fruit, choosing clothing, and reading traffic lights. Color blindness may make some aca ...
that is caused by damage to the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
. Damage is most commonly localized to visual area V4 of the
visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...
(the major part of the
colour center The colour centre is a region in the brain primarily responsible for visual perception and cortical processing of colour signals received by the eye, which ultimately results in colour vision. The colour centre in humans is thought to be located ...
), which receives information from the parvocellular pathway involved in color processing. It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth. If there is unilateral damage, a loss of color perception in only half of the visual field may result; this is known as hemiachromatopsia. Cerebral achromats usually do not experience the other major symptoms of congenital achromatopsia, since
photopic vision Photopic vision is the vision of the eye under well-lit conditions ( luminance levels from 10 to 108  cd/m2). In humans and many other animals, photopic vision allows color perception, mediated by cone cells, and a significantly higher vi ...
is still functions. Color agnosia involves having difficulty recognizing colors, while still being able to perceive them as measured by a color matching or categorizing task.


Terminology


References


Footnotes


Sources

* * * * * * * * * * * *


External links


Achromatopsia
at MedicineNet
Achromatopsia
at
Merriam-Webster Merriam-Webster, Inc. is an American company that publishes reference books and is especially known for its dictionaries. It is the oldest dictionary publisher in the United States. In 1831, George and Charles Merriam founded the company as ...

Achromatopsia
at NCBI
The Achromatopsia Network
- an archive of information about Achromatopsia and advice on coping with the condition. {{Authority control Agnosia Channelopathies Color vision Rare diseases Visual disturbances and blindness Visual perception Visual system