Achromatopsia
Other names	Rod Monochromacy
Specialty	Ophthalmology
Symptoms	Monochromacy,Day blindness,Photophobia
Causes	Congenital malfunction of theVisual phototransduction pathway
Diagnostic method	Electroretinography
Frequency	⁠1/30,000⁠× 100% =0.0033%

Achromatopsia, also known asrod monochromacy, is a medical syndrome that exhibits symptoms relating to five conditions, most notablymonochromacy. Historically, the name referred to monochromacy in general, but now typically refers only to anautosomal recessive congenitalcolor vision condition. The term is also used to describecerebral achromatopsia, thoughmonochromacy is usually the only common symptom. The conditions include:monochromatic color blindness, poor visual acuity, andday-blindness. The syndrome is also present in anincomplete form that exhibits milder symptoms, including residual color vision. Achromatopsia is estimated to affect 1 in 30,000 live births worldwide.

The five symptoms associated with achromatopsia are:^{[citation needed]}

1. Color blindness – usuallymonochromacy
2. Reducedvisual acuity – uncorrectable with lenses
3. Hemeralopia – with the subject exhibitingphotophobia
4. Nystagmus
5. Iris operating abnormalities

The syndrome is typically first noticed in children around six months of age due to theirphotophobia or theirnystagmus. 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.^{[citation needed]}

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.^{[citation needed]} Thefundus of the eye appears completely normal.^{[citation needed]}

Achromatopsia can be classified ascomplete orincomplete. 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.^{[citation needed]}

Achromatopsia is sometimes calledrod monochromacy (as opposed toblue cone monochromacy), as achromats exhibit a complete absence ofcone cell activity viaelectroretinography inphotopic lighting. There are multiplegenetic causes of achromatopsia, including mutations in:

• the cone cellcyclic nucleotide-gated ion channel proteinsCNGA3 (ACHM2^[1][2]) and CNGB3 (ACHM3)
• the conephotoreceptortransducin (GNAT2, ACHM4^[3]),
• subunits of conephosphodiesterasePDE6C (ACHM5^[4])^[5] andPDEH (ACHM6, OMIM 610024), and
• ATF6 (ACHM7^[6]).

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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.^{[citation needed]}

In general, the molecular pathomechanism of achromatopsia is either the inability to properly control or respond to altered levels ofcGMP; particularly important invisual perception as its level controls the opening ofcyclic nucleotide-gated ion channels (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resultinghyperpolarization and cessation ofglutamaterelease. Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, incone cells. 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⁺ andCa²⁺), relative efficacy of cAMP/cGMP activation, decreased outwardrectification, current flickering, and sensitivity to block byL-cis-diltiazem.^{[citation needed]}

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 thecone celltransducin, GNAT2. Mutations in GNAT2 tend to result in a truncated and, presumably, non-functional protein, thereby preventing alteration of cGMP levels byphotons. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsiaphenotype.^{[citation needed]}

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.^{[citation needed]}

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 forCyclic guanosine monophosphate. Others include the introduction of a sub-conductance, altered single-channel gating kinetics, and increasedcalcium permeability.^{[citation needed]}

When mutant T369S channels coassemble with CNGB3, however, the only remaining aberration is increased calcium permeability.^[7] 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.^[8] Such loss of function will undoubtedly negate thecone 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.^[7]

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 inhaploinsufficiency, though in some cases the truncated proteins may be able to coassemble with wild-type channels in adominant negative fashion. The most prevalent ACHM3 mutation, T383IfsX12, results in a non-functional truncated protein that does not properly traffic to thecell membrane.^[9][10]

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.^[10] The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP.^[9][10] 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.^{[citation needed]}

Upon activation by light,cone opsin causes the exchange of GDP for GTP in the guanine nucleotide binding protein (G-protein) α-transducing activity polypeptide 2 (GNAT2). This causes the release of the activated α-subunit from the inhibitory β/γ-subunits. This α-subunit then activates aphosphodiesterase 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 orphotoreceptormembrane hyperpolarization.^{[citation needed]}

As achromatopsia is linked to only a few single-gene mutations, it is a good candidate for gene therapy.Gene therapy 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.^[11] In July 2023, a study found positive but limited improvements on congenital CNGA3 achromatopsia.^[12][13]

Since 2003, a cybernetic device called theeyeborg has allowed people to perceive color through sound waves. This form ofSensory substitution maps thehue perceived by a camera worn on the head to apitch experienced through bone conduction according to asonochromatic scale.^[14] This allows achromats (or even the totally blind) to perceive – or estimate – the color of an object. Achromat and artistNeil 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 a 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.^[15]

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 ofcolored 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 ofmonocular lenses and theSeeKey. In some US states, achromats can use a red filter while driving to determine the color of a traffic light.^[16]
• 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.^[17]
• 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.^[16]

Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people.^[18]

However, on the smallMicronesian atoll ofPingelap, approximately five percent of the atoll's 3,000 inhabitants are affected.^[19][20] This is the result of apopulation bottleneck caused by a typhoon and ensuing famine in the 1770s, which killed all but about twenty islanders, including one who was heterozygous for achromatopsia.^[21]

The people of this region have termed achromatopsia "maskun", which literally means "not see" inPingelapese.^[22] This unusual population drew neurologistOliver Sacks to the island for which he wrote his 1997 book,The Island of the Colorblind.^[23]

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 asx-linked achromatopsia,sex-linked achromatopsia oratypical achromatopsia. BCM stems from mutations or deletions of theOPN1LW andOPN1MW genes, both on theX chromosome. As a recessive x-linked condition, BCM disproportionately affects males, unlike typical achromatopsia.^{[citation needed]}

Cerebral achromatopsia is a form of acquiredcolor blindness that is caused by damage to thecerebral cortex. Damage is most commonly localized to visual areaV4 of thevisual cortex (the major part of thecolour center), which receives information from the parvocellular pathway involved in color processing.^{[citation needed]} It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth.^[24] If there is unilateral damage, a loss of color perception in only half of the visual field may result; this is known as hemiachromatopsia.^[25] Cerebral achromats usually do not experience the other major symptoms of congenital achromatopsia, sincephotopic vision still functions.^{[citation needed]}

Color agnosia involves having difficulty recognizing colors, while still being able to perceive them as measured by a color matching or categorizing task.^[26]

• Elham Mahamid Ruzin (born 1990), Israeli Paralympic goalball player

Look upachromatopsia in Wiktionary, the free dictionary.

• AchromatopsiaArchived 2020-02-23 at theWayback Machine atMedicineNet
• Achromatopsia atMerriam-Webster
• Achromatopsia atNCBI
• The Achromatopsia Network – an archive of information about Achromatopsia and advice on coping with the condition.

• Agnosia
• Channelopathies
• Color vision
• Rare diseases
• Visual disturbances and blindness
• Visual perception
• Visual system

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