Achromatopsia
Encyclopedia
Achromatopsia is a medical syndrome that exhibits symptoms relating to at least five separate individual disorders. Although the term may refer to acquired disorders such as color agnosia
and cerebral achromatopsia
, it typically refers to an autosomal recessive congenital color vision disorder, the inability to perceive color and to achieve satisfactory visual acuity at high light levels (typically exterior daylight). The syndrome is also present in an incomplete form which is more properly defined as dyschromatopsia. The only estimate of its relative occurrence of 1:33,000 in the general population dates from the 1960s or earlier.
There is some discussion as to whether achromats can see color or not. As illustrated in The Island of the Colorblind
by Oliver Sacks
, some achromats cannot see color, only black, white, and shades of grey. With 5 different genes currently known to cause similar symptoms, it may be that some do see marginal levels of color differentiation due to different gene characteristics. With such small sample sizes and low response rates, it is difficult to accurately diagnose the 'typical achromatic conditions'. If the light level during testing is optimized for them, they may achieve corrected visual acuity of 20/100 to 20/150 at lower light levels, regardless of the absence of color. One common trait is hemeralopia
or blindness in full sun. In patients with achromatopsia, the cone system and fibres carrying colour information remain intact. This indicates that the mechanism used to construct colours is defective.
The congenital forms of the disorder are considered stationary and do not worsen with age.
The five symptoms associated with achromatopsia/dyschromatopsia are:
A sixth symptom associated with achromatopsia/dychromatopsia is seldom reported. Many sufferers are unaware of the three-dimensional aspect of their visual system. They frequently fail to observe any of the stereographic features of a scene.
The syndrome of achromatopsia/dyschromatopsia is poorly described in current medical and neuro-ophthalmological texts. It became a common term following the popular book by the neuroscientist Oliver Sacks, "The Island of the Colorblind," in 1997. Up to that time most color-blind subjects were described as achromats or achromatopes. Those with a lesser degree of color perception abnormality were described as either protanopes, deuteranopes or tetartanopes (historically tritanopes).
Achromatopsia has also been called rod monochromacy and total congenital color blindness. Individuals with the congenital form of this disorder show complete absence of cone cell
activity via electroretinography
at high light levels. There are at least four genetic causes
of congenital ACHM, two of which involve cyclic nucleotide-gated ion channel
s (ACHM2/ACHM3), a third involves the cone
photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown.
aberrations. Included among these aberrations are greatly decreased visual acuity
(<0.1 or 20/200) in daylight Hemeralopia
, nystagmus, and severe photophobia
. The fundus
of the eye appears completely normal.
of the mid brain) or the cerebral cortex
(the new brain).
Thalamic achromatopsia/dyschromatopsia is caused by damage to the thalamus; it is most frequently caused by tumor growth since the thalamus is well protected from external damage.
Cerebral achromatopsia is a form of acquired color blindness
that is caused by damage to the cerebral cortex
of the brain, rather than abnormalities in the cells of the eye's retina
. It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth.
s to properly respond to light input by hyperpolarizing
. Known genetic causes of this are mutations in the cone cell cyclic nucleotide-gated ion channel
s CNGA3 (ACHM2) and CNGB3 (ACHM3) as well as the cone cell transducin
, GNAT2 (ACHM4).
A fourth genetic cause (ACHM5, OMIM 613093) has been discovered in 2009. It is a mutation of gene PDE6C, located on chromosome locus 10, 10q24. It is estimated than less than 2% of achromatopsias are caused by a mutation in this gene.
In general, the molecular pathomechanism of ACHM is either the inability to properly control or respond to altered levels of cGMP
. cGMP is particularly important in visual perception as its level controls the opening of cyclic nucleotide-gated ion channel
s (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization
and cessation of glutamate release. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in cone cell
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
, 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
transducin
, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels by photon
s. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia phenotype
.
. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increased calcium
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 ACHM, 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
'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.
, 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 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.
Upon activation by light, rhodopsin
causes the exchange of GDP for GTP in the guanine nucleotide binding protein (G-protein) α-transducin
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
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, table 3, all result in truncated proteins. Presumably, then, these proteins are non-functional and, consequently, rhodopsin that has been activated by light does not lead to altered cGMP levels or photoreceptor
membrane hyperpolarization
.
that allows people to perceive colour through sound waves. Achromatopsic artist Neil Harbisson
was the first to use such a device in early 2004, the eyeborg
allowed him start painting in color by memorizing the sound of each colour.
Moreover, there is some research on gene therapy for animals with achromatopsia, with positive results on mice and young dogs, but less effectiveness on older dogs. However, no experiments have been made on humans. There are many challenges to conducting gene therapy on humans. See Gene therapy for color blindness
for more details about it.
n atoll
of Pingelap
approximately 5% of the atoll's 3000 inhabitants are afflicted.
n atoll
of Pingelap
. The typhoon and ensuing famine
left only around 20 survivors, one of whom was heterozygous for achromatopsia. Four generations after this population bottleneck
the prevalence of achromatopsia is 5% with a further 30% as carriers. 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 Colour-blind. Steppenwolf
front man John Kay
suffers from achromatopsia.
Color agnosia
Color agnosia , is a medical or psychological condition that prevents a person from correctly associating hue names with common objects. The sufferer retains the ability of distinguishing hues...
and cerebral achromatopsia
Cerebral achromatopsia
Cerebral achromatopsia is a type of color-blindness that is caused by damage to the cerebral cortex of the brain, rather than abnormalities in the cells of the eye's retina. It is often confused with congenital achromatopsia. Cerebral achromatopsia differs because it is caused only by trauma or...
, it typically refers to an autosomal recessive congenital color vision disorder, the inability to perceive color and to achieve satisfactory visual acuity at high light levels (typically exterior daylight). The syndrome is also present in an incomplete form which is more properly defined as dyschromatopsia. The only estimate of its relative occurrence of 1:33,000 in the general population dates from the 1960s or earlier.
There is some discussion as to whether achromats can see color or not. As illustrated in The Island of the Colorblind
The Island of the Colorblind
The Island of the Colorblind is a book by neurologist Oliver Sacks about achromatopsia on the Micronesian atoll of Pingelap. The second half of the book is devoted to the mystery of Lytico-Bodig disease in Guam.-External links:*...
by Oliver Sacks
Oliver Sacks
Oliver Wolf Sacks, CBE , is a British neurologist and psychologist residing in New York City. He is a professor of neurology and psychiatry at Columbia University, where he also holds the position of Columbia Artist...
, some achromats cannot see color, only black, white, and shades of grey. With 5 different genes currently known to cause similar symptoms, it may be that some do see marginal levels of color differentiation due to different gene characteristics. With such small sample sizes and low response rates, it is difficult to accurately diagnose the 'typical achromatic conditions'. If the light level during testing is optimized for them, they may achieve corrected visual acuity of 20/100 to 20/150 at lower light levels, regardless of the absence of color. One common trait is hemeralopia
Hemeralopia
Hemeralopia is the inability to see clearly in bright light and is the exact opposite of Nyctalopia . Hemera was the Greek goddess of day and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors...
or blindness in full sun. In patients with achromatopsia, the cone system and fibres carrying colour information remain intact. This indicates that the mechanism used to construct colours is defective.
Classification
- Acquired achromatopsia (Cerebral achromatopsiaCerebral achromatopsiaCerebral achromatopsia is a type of color-blindness that is caused by damage to the cerebral cortex of the brain, rather than abnormalities in the cells of the eye's retina. It is often confused with congenital achromatopsia. Cerebral achromatopsia differs because it is caused only by trauma or...
) - Congenital/inherited achromatopsia
- Complete/typical achromatopsia
- Incomplete/atypical achromatopsia or Incomplete/atypical dyschromatopsia
- Achromatopsia–The complete lack of the perception of color in a subject, seeing only in black, white, and shades of grey.
- AmblyopiaAmblyopiaAmblyopia, also known as lazy eye, is a disorder of the visual system that is characterized by a vision deficiency in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities of the eye...
–Defined conceptually by Duke-ElderStewart Duke-ElderSir William Stewart Duke-Elder, GCVO, DSc, LLD, MD, PhD, FRCP, FRCS, FRS , a Scottish ophthalmologist born in Tealing near Dundee, was a dominant force in his field for more than a quarter of a century...
(1973) as a monocular acuity deficit which is not due to refractive error or any organic abnormality. A neural condition. Poor spatial performance of the precision optical servomechanism of the eyes at nominal illumination levels without any morphological cause. Lazy eyeLazy EyeLazy eye may refer to:* Amblyopia, a visual disorder* Strabismus, the most common cause of amblyopia* "Lazy Eye" * "Lazy Eye"...
. - HemeralopiaHemeralopiaHemeralopia is the inability to see clearly in bright light and is the exact opposite of Nyctalopia . Hemera was the Greek goddess of day and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors...
–Reduced visual capacity in bright light. Colloquially, day-blindness. - Nystagmus–This term is used variously to describe both normal and pathological conditions related to the oculomotor system. In the current context, it is a pathological condition involving an uncontrolled oscillatory movement of the eyes during which the amplitude of oscillationOscillationOscillation is the repetitive variation, typically in time, of some measure about a central value or between two or more different states. Familiar examples include a swinging pendulum and AC power. The term vibration is sometimes used more narrowly to mean a mechanical oscillation but sometimes...
is quite noticeable and the frequency of the oscillation tends to be quite low. - PhotophobiaPhotophobiaPhotophobia is a 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 actual physical photosensitivity of the eyes, though the term...
–The avoidance of bright light by those suffering from hemeralopiaHemeralopiaHemeralopia is the inability to see clearly in bright light and is the exact opposite of Nyctalopia . Hemera was the Greek goddess of day and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors...
.
Signs and symptoms
The syndrome is frequently noticed first in children around six months of age by their photophobic activity and/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 6–7 years of life (but remain near 20/200).The congenital forms of the disorder are considered stationary and do not worsen with age.
The five symptoms associated with achromatopsia/dyschromatopsia are:
- Achromatopia
- AmblyopiaAmblyopiaAmblyopia, also known as lazy eye, is a disorder of the visual system that is characterized by a vision deficiency in an eye that is otherwise physically normal, or out of proportion to associated structural abnormalities of the eye...
(reduced visual acuity) - HemeralopiaHemeralopiaHemeralopia is the inability to see clearly in bright light and is the exact opposite of Nyctalopia . Hemera was the Greek goddess of day and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors...
(with the subject exhibiting photophobia) - Nystagmus
- IrisIris (anatomy)The iris is a thin, circular structure in the eye, responsible for controlling the diameter and size of the pupils and thus the amount of light reaching the retina. "Eye color" is the color of the iris, which can be green, blue, or brown. In some cases it can be hazel , grey, violet, or even pink...
operating abnormalities
A sixth symptom associated with achromatopsia/dychromatopsia is seldom reported. Many sufferers are unaware of the three-dimensional aspect of their visual system. They frequently fail to observe any of the stereographic features of a scene.
The syndrome of achromatopsia/dyschromatopsia is poorly described in current medical and neuro-ophthalmological texts. It became a common term following the popular book by the neuroscientist Oliver Sacks, "The Island of the Colorblind," in 1997. Up to that time most color-blind subjects were described as achromats or achromatopes. Those with a lesser degree of color perception abnormality were described as either protanopes, deuteranopes or tetartanopes (historically tritanopes).
Achromatopsia has also been called rod monochromacy and total congenital color blindness. Individuals with the congenital form of this disorder show complete absence of cone cell
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
activity via electroretinography
Electroretinography
Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors , inner retinal cells , and the ganglion cells. Electrodes are usually placed on the cornea and the skin near the eye, although it is possible to record the ERG from skin electrodes...
at high light levels. There are at least four genetic causes
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of congenital ACHM, two of which involve cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...
s (ACHM2/ACHM3), a third involves the cone
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown.
Complete Achromatopsia
Aside from a complete inability to see color, individuals with complete achromatopsia have a number of other ophthalmologicOphthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...
aberrations. Included among these aberrations are greatly decreased visual acuity
Visual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
(<0.1 or 20/200) in daylight Hemeralopia
Hemeralopia
Hemeralopia is the inability to see clearly in bright light and is the exact opposite of Nyctalopia . Hemera was the Greek goddess of day and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors...
, nystagmus, and severe photophobia
Photophobia
Photophobia is a 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 actual physical photosensitivity of the eyes, though the term...
. The fundus
Fundus (eye)
The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula and fovea, and posterior pole. The fundus can be viewed with an ophthalmoscope. The term may also be inclusive of Bruch's membrane and the choroid.The color of the fundus varies...
of the eye appears completely normal.
Incomplete Achromatopsia (Dyschromatopsia)
In general, symptoms of incomplete achromatopsia are similar to those of complete achromatopsia except in a diminished form. Individuals with incomplete achromatopsia have reduced visual acuity with or without nystagmus or photophobia. Furthermore, these individuals show only partial impairment of cone cell function but again have retained rod cell function.Acquired
Acquired achromatopsia/dyschromatopsia is a condition associated with damage to the diencephalon (primarily the thalamusThalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
of the mid brain) or the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
(the new brain).
Thalamic achromatopsia/dyschromatopsia is caused by damage to the thalamus; it is most frequently caused by tumor growth since the thalamus is well protected from external damage.
Cerebral achromatopsia is a form of acquired color blindness
Color blindness
Color blindness or color vision deficiency is the inability or decreased ability to see color, or perceive color differences, under lighting conditions when color vision is not normally impaired...
that is caused by damage to the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
of the brain, rather than abnormalities in the cells of the eye's retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
. It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth.
Congenital
The known causes of the congenital forms of achromatopsia are all due to malfunction of the retinal phototransduction pathway. Specifically, this form of ACHM seems to result from the inability of cone cellCone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
s to properly respond to light input by hyperpolarizing
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
. Known genetic causes of this are mutations in the cone cell cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...
s CNGA3 (ACHM2) and CNGB3 (ACHM3) as well as the cone cell transducin
Transducin
Transducin is a heterotrimeric G protein that is naturally expressed in vertebrate retina rods and cones .- Mechanism of action :...
, GNAT2 (ACHM4).
A fourth genetic cause (ACHM5, OMIM 613093) has been discovered in 2009. It is a mutation of gene PDE6C, located on chromosome locus 10, 10q24. It is estimated than less than 2% of achromatopsias are caused by a mutation in this gene.
Pathophysiology
The hemeralopic aspect of ACHM can be diagnosed non-invasively using electroretinography. The response at low (scotopic) and median (mesotopic) light levels will be normal but the response under high light level (photopic) conditions will be absent. The mesotopic level is approximately 100 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 ACHM is either the inability to properly control or respond to altered levels of cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
. cGMP is particularly important in visual perception as its level controls the opening of cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...
s (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
and cessation of glutamate release. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in cone cell
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
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+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
vs. K+
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
and Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
), relative efficacy of cAMP/cGMP activation, decreased outward rectification
Rectification
Rectification has the following technical meanings:* Rectification, in astrology* Rectification , a concept found in biology and industrial chemistry* Chinese history: see Cheng Feng...
, current flickering, and sensitivity to block by L-cis-diltiazem
Diltiazem
Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
. 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 cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
transducin
Transducin
Transducin is a heterotrimeric G protein that is naturally expressed in vertebrate retina rods and cones .- Mechanism of action :...
, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels by photon
Photon
In physics, a photon is an elementary particle, the quantum of the electromagnetic interaction and the basic unit of light and all other forms of electromagnetic radiation. It is also the force carrier for the electromagnetic force...
s. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
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, see table 1, 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 monophosphateCyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increased calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
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 ACHM, 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 cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
'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.
| Mutation | Region | Functional? (known or predicted) |
Effect | References | |
|---|---|---|---|---|---|
| Nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... |
Amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
||||
| c.C67T | p.R23X | N-Term | No? | ||
| c.148insG | p. I50DfsX59 | N-Term | No? | ||
| c.A485T | p.D162V | N-Term | |||
| c.C488T | p.P163L | N-Term | , | ||
| c.A542G | p.Y181C | S1 | No | Does not properly traffic out of the endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
, |
| c.A544T | p.N182Y | S1 | No | Does not properly traffic out of the endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
, |
| c.C556T | p. L186F | S1 | No | Does not properly traffic out of the endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
, |
| c.G572A | p. C191Y | S1-2 | No | Does not properly traffic out of the endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
, |
| c.G580A | p.E194K | S1-2 | No | Does not properly traffic out of the endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
|
| c.C586T | p.G196X | S1-2 | No? | ||
| c.C661T | p.R221X | S2 | No? | ||
| c.C667T | p.R223W | S2-3 | , | ||
| c.C671G | p.T224R | S2-3 | No | No current | , |
| c.G778A | p.D260N | S3 | |||
| c.G800A | p.G267D | S3-4 | |||
| c.C829T | p.R277C | S4 | |||
| c.G830A | p.R277H | S4 | |||
| c.C847T | p.R283Q | S4 | , | ||
| c.G848A | p.R283W | S4 | , | ||
| c.C872G | p.T291R | S4 | , | ||
| c.934_936del | p. 312delI | S5 | |||
| c.G947A | p.W316X | S5 | No? | ||
| c.T1021C | p.S341P | Pore | |||
| c.C1106G | p.T369S | pore | Yes | Increased calcium Calcium Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust... influx |
, |
| c.C1114T | p.P372S | Pore | |||
| c.T1139C | p.F380S | Pore | |||
| c.T1217C | p.M406T | S6 | |||
| c.C1228T | p.R410W | C-term | , | ||
| c.C1279T | p.R427C | C-term | |||
| c.C1306T | p.R436W | C-term | , | ||
| c.G1320A | p.W440X | C-term | No? | ||
| c.1350insG | p. V451GfsX453 | C-term | No? | ||
| c.A1412G | p.N471S | C-term | |||
| c.1443insC | p. I482HfsX5 | C-term | No? | ||
| c.A1454T | p.D485V | C-term | |||
| c.G1529C | p. C510S | cNMP | |||
| c.G1538A | p.G513E | cNMP | |||
| c.G1547A | p.G516E | cNMP | |||
| c.T1565C | p. I522T | cNMP | |||
| c.G1574A | p.G525D | cNMP | |||
| c.G1585A | p. V529M | cNMP | , | ||
| c.C1609T | p.Q537X | cNMP | No? | , | |
| c.C1641A | p.F547L | cNMP | , | ||
| c.G1642A | p.G548R | cNMP | |||
| c.G1669A | p.G557R | cNMP | , | ||
| c.G1688A | p.R563H | cNMP | |||
| c.C1694T | p.T565M | cNMP | |||
| c.G1706A | p.R569H | cNMP | , | ||
| c.A1718G | p.Y573C | cNMP | |||
| c.G1777A | p.E593K | cNMP | |||
| c.C1963T | p.Q655X | C-term | |||
| Abbreviations: SX, transmembrane segment number X; SX-Y, linker region between transmembrane segments X and Y; cNMP, cyclic nucleotide (cAMP or cGMP) binding region. | |||||
ACHM3
While very few mutations in CNGB3 have been characterized, the vast majority of them result in truncated channels that are presumably non-functional, table 2. This will largely result in haploinsufficiencyHaploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
, 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
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. 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.
| Mutation | Region | Functional? (known or predicted) |
Effect | References | |
|---|---|---|---|---|---|
| Nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... |
Amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
||||
| c.29_30insA | p.K10fsX9 | N-Term | No? | ||
| c.C112T | p.Q38X | N-Term | No? | ||
| c.C391T | p.Q131X | N-Term | No? | ||
| c.A442G | p.K148E | N-Term | |||
| c.446_447insT | p.K149NfsX29 | N-Term | No? | ||
| c.C467T | p.S156F | N-Term | |||
| c.595delG | p.E199SfsX2 | N-Term | No? | ||
| c.C607T | p.R203X | N-Term | No? | , | |
| c.G644-1C | Splicing Splicing (genetics) In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation... |
No? | |||
| c.C646T | p.R216X | N-Term | No? | ||
| c.682_683insG | p.A228GfsX2 | S1 | No? | ||
| c.G702A | p.W234X | S1 | No? | ||
| c.706_707delinsTT | p. I236FfsX25 | S1 | No? | ||
| c.819_826del | p.P273fsX13 | S2-3 | No? | , | |
| c.882_892delinsT | p.R295QfsX9 | S2-3 | No? | ||
| c.C926T | p.P309L | S3 | |||
| c.T991-3G | Splicing Splicing (genetics) In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation... |
No? | |||
| c.G1006T | p.E336X | S4 | No? | , | |
| c.C1063T | p.R355X | S5 | No? | ||
| c.G1119A | p.W373X | S5 | No? | ||
| c.1148delC | p.T383IfsX12 | Pore | No | Does not traffic to the surface | ,,, |
| c.G1208A | p.R403Q | Pore | Yes | Increased outward rectification, increased cGMP affinity | |
| c.G1255T | p.E419X | Pore | No? | ||
| c.1298_1299del | p. V433fsX27 | S6 | No? | ||
| c.C1304T | p.S435F | S6 | Yes | Increased affinity for cAMP and cGMP, decreased surface expression, altered ion permeability, decreased single channel conductance, decreased sensitivity for diltiazem Diltiazem Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia.... |
, |
| c.C1432T | p.R478X | C-term | No? | ||
| c.G1460A | p.W487X | C-term | No? | ||
| c.1573_1574delinsTT | p.F525N | C-term | Yes | Increased surface expression in oocyte Oocyte An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic... s, decreased outward rectification, increased cGMP and cAMP affinity |
, |
| c.G1578+1A | Splicing Splicing (genetics) In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation... |
No? | , | ||
| c.T1635A | p.Y545X | cNMP | No? | ||
| c.G1781+1C | Splicing Splicing (genetics) In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation... |
No? | |||
| c.G1781+1A | Splicing Splicing (genetics) In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation... |
No? | |||
| c.2160_2180del | p. 720_726del | C-term | |||
| Abbreviations: SX, transmembrane segment number X; SX-Y, linker region between transmembrane segments X and Y; cNMP, cyclic nucleotide (cAMP or cGMP) binding region. | |||||
ACHM4
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
causes the exchange of GDP for GTP in the guanine nucleotide binding protein (G-protein) α-transducin
Transducin
Transducin is a heterotrimeric G protein that is naturally expressed in vertebrate retina rods and cones .- Mechanism of action :...
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
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
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, table 3, all result in truncated proteins. Presumably, then, these proteins are non-functional and, consequently, rhodopsin that has been activated by light does not lead to altered cGMP levels or photoreceptor
Photoreceptor protein
Photoreceptors are light-sensitive proteins involved in the sensing and response to light in a variety of organisms. Some examples are rhodopsin in the photoreceptor cells of the vertebrate retina, phytochrome in plants, and bacteriorhodopsin and bacteriophytochromes in some bacteria...
membrane hyperpolarization
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
.
| Mutation | Functional? (predicted) |
References | |
|---|---|---|---|
| Nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... |
Amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
||
| c.C235T | p.Q79X | No? | |
| c.285_291del | p.Y95fsX61 | No? | |
| IVS3+365_IVS4+974del | p.A101fsX12 | No? | |
| c.503_504insT | p. L168fsX3 | No? | |
| c.802_803insTCAA | p. L268fsX9 | No? | |
| c.955del | p. I319SfsX5 | No? | |
Management
There is generally no treatment to cure achromatopsia. However, since 2003, there is a cybernetic device called eyeborgEyeborg
An eyeborg or eye-borg is a cybernetic body apparatus which typically fits on the wearer's head, and is designed to allow people to perceive color through sound waves. It is mostly used by blind people or by people with visual impairments such as color blindness or achromatopsia...
that allows people to perceive colour through sound waves. Achromatopsic artist Neil Harbisson
Neil Harbisson
Neil Harbisson is a Catalan raised, Northern Ireland born artist, musician and performer best known for his self-extended ability to hear colours. In 2004 he became the first person in the world to wear an eyeborg. The inclusion of the eyeborg on his passport photo has been claimed by some to be...
was the first to use such a device in early 2004, the eyeborg
Eyeborg
An eyeborg or eye-borg is a cybernetic body apparatus which typically fits on the wearer's head, and is designed to allow people to perceive color through sound waves. It is mostly used by blind people or by people with visual impairments such as color blindness or achromatopsia...
allowed him start painting in color by memorizing the sound of each colour.
Moreover, there is some research on gene therapy for animals with achromatopsia, with positive results on mice and young dogs, but less effectiveness on older dogs. However, no experiments have been made on humans. There are many challenges to conducting gene therapy on humans. See Gene therapy for color blindness
Gene therapy for color blindness
Gene therapy for color blindness is an experimental gene therapy aiming to convert congenitally colorblind individuals to trichromats by introducing a photopigment gene that they lack. Though partial color blindness is considered only a mild disability and is controversial whether it is even a...
for more details about it.
Epidemiology
Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people (0.0033%). However, in the small MicronesiaMicronesia
Micronesia is a subregion of Oceania, comprising thousands of small islands in the western Pacific Ocean. It is distinct from Melanesia to the south, and Polynesia to the east. The Philippines lie to the west, and Indonesia to the southwest....
n atoll
Atoll
An atoll is a coral island that encircles a lagoon partially or completely.- Usage :The word atoll comes from the Dhivehi word atholhu OED...
of Pingelap
Pingelap
Pingelap is an atoll in the Pacific Ocean, part of Pohnpei state of the Federated States of Micronesia, consisting of three islands: Pingelap Island, Sukoru and Daekae, linked by a reef system and surrounding a central lagoon, although only Pingelap Island is inhabited. The entire system has a land...
approximately 5% of the atoll's 3000 inhabitants are afflicted.
Society and culture
In approximately 1775 Typhoon Lengkieki struck and devastated the MicronesiaMicronesia
Micronesia is a subregion of Oceania, comprising thousands of small islands in the western Pacific Ocean. It is distinct from Melanesia to the south, and Polynesia to the east. The Philippines lie to the west, and Indonesia to the southwest....
n atoll
Atoll
An atoll is a coral island that encircles a lagoon partially or completely.- Usage :The word atoll comes from the Dhivehi word atholhu OED...
of Pingelap
Pingelap
Pingelap is an atoll in the Pacific Ocean, part of Pohnpei state of the Federated States of Micronesia, consisting of three islands: Pingelap Island, Sukoru and Daekae, linked by a reef system and surrounding a central lagoon, although only Pingelap Island is inhabited. The entire system has a land...
. The typhoon and ensuing famine
Famine
A famine is a widespread scarcity of food, caused by several factors including crop failure, overpopulation, or government policies. This phenomenon is usually accompanied or followed by regional malnutrition, starvation, epidemic, and increased mortality. Every continent in the world has...
left only around 20 survivors, one of whom was heterozygous for achromatopsia. Four generations after this population bottleneck
Population bottleneck
A population bottleneck is an evolutionary event in which a significant percentage of a population or species is killed or otherwise prevented from reproducing....
the prevalence of achromatopsia is 5% with a further 30% as carriers. The people of this region have termed achromatopsia "maskun", which literally means "not see" in Pingelapese. This unusual population drew neurologist
Neurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...
Oliver Sacks
Oliver Sacks
Oliver Wolf Sacks, CBE , is a British neurologist and psychologist residing in New York City. He is a professor of neurology and psychiatry at Columbia University, where he also holds the position of Columbia Artist...
to the island for which he wrote his 1997 book, The Island of the Colour-blind. Steppenwolf
Steppenwolf (band)
Steppenwolf are a Canadian-American rock group that was prominent in the late 1960s. The group was formed in 1967 in Los Angeles by vocalist John Kay, guitarist Michael Monarch, bassist Rushton Moreve, keyboardist Goldy McJohn and drummer Jerry Edmonton after the dissolution of Toronto group The...
front man John Kay
John Kay (musician)
John Kay is a German-Canadian singer, songwriter and guitarist known as the frontman of Steppenwolf...
suffers from achromatopsia.
External links
- GeneReviews/NIH/NCBI/UW entry on Achromatopsia
- OMIM entries on Achromatopsia
- Achromatopsia.info - The most comprehensive website on treating and living with achromatopsia