Medicine:Achromatopsia

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:

1. Color blindness – usually monochromacy
2. Reduced visual acuity – uncorrectable with lenses
3. Hemeralopia – with the subject exhibiting photophobia
4. Nystagmus

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 of the eye appears completely normal.{{citation needed|date=September 202

Cause

Achromatopsia is sometimes called rod monochromacy (as opposed to blue cone monochromacy), as achromats exhibit a complete absence of cone cell activity via electroretinography in photopic lighting. There are multiple genetic causes of achromatopsia, including mutations in:

• the cone cell cyclic nucleotide-gated ion channel proteins CNGA3 (ACHM2) and CNGB3 (ACHM3)
• the cone photoreceptor transducin (GNAT2, ACHM4),
• subunits of cone phosphodiesterase PDE6C (ACHM5) and PDEH (ACHM6, OMIM 610024), and
• ATF6 (ACHM7).

Pathophysiology

ACHM2

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'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, 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.

Management

Gene therapy

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. In July 2023, a study found positive but limited improvements on congenital CNGA3 achromatopsia.

Eyeborg

Main article: 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 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.

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 Micronesian atoll of Pingelap, approximately five percent of the atoll's 3,000 inhabitants are affected. This is the result of a population 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.

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

Main article: Medicine:Blue cone monochromacy

Cerebral achromatopsia

Cerebral achromatopsia is a form of acquired color blindness that is caused by damage to the cerebral cortex. Damage is most commonly localized to visual area V4 of the visual cortex (the major part of the colour center), 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 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

Monochromacy

Complete lack of the perception of color in a subject, seeing only in black, white, and shades of grey.

Hemeralopia

Reduced visual capacity in bright light, i.e. day-blindness.

Nystagmus

Term 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 oscillation is quite noticeable and the frequency of the oscillation tends to be quite low.

Photophobia

Avoidance of bright light by those who have hemeralopia.

See also

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

References

Sources

• Bright, S. R. (2005). "Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels". Mol. Vis. 11: 1141–1150. PMID 16379026. 
• Brody, J. A. (1970). "Hereditary blindness among Pingelapese people of Eastern Caroline Islands". Lancet 295 (7659): 1253–1257. doi:10.1016/s0140-6736(70)91740-x. PMID 4192495. 
• Corn, A. N. (2010). Foundations of low vision: clinical and functional perspectives. Arlington: AFB Press. ISBN 9780891288831. 
• Hussels, I. E. (1972). "Pingelap and Mokil Atolls: achromatopsia". Am. J. Hum. Genet. 24 (3): 304–309. PMID 4555088. 
• Morton, N. E. (1972). "Pingelap and Mokil Atolls: historical genetics". Am. J. Hum. Genet. 24 (3): 277–289. PMID 4537352. 
• Patel, K. A. (2005). "Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel". Investig. Ophthalmol. Vis. Sci. 46 (7): 2282–2290. doi:10.1167/iovs.05-0179. PMID 15980212. 
• Pearlman, E. (2015). "I, Cyborg". PAJ 37 (2): 84–90. doi:10.1162/PAJJ_a_00264. 
• Peng, C. (2003). "Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels". J. Biol. Chem. 278 (36): 34533–34540. doi:10.1074/jbc.M305102200. PMID 12815043. 
• Ronchi, A. M. (2009). eCulture: cultural content in the digital age. Berlin: Springer. ISBN 9783540752738. 
• Thiadens, A. A. H. J. (2009). "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders". Am. J. Hum. Genet. 85 (2): 240–247. doi:10.1016/j.ajhg.2009.06.016. PMID 19615668. 
• Thiadens, A. A. H. J. (2011). Genetic etiology and clinical consequences of cone disorders. Erasmus University Rotterdam. ISBN 9789461690579. 
• Tränkner, D. (2004). "Molecular basis of an inherited form of incomplete achromatopsia". J. Neurosci. 24 (1): 138–147. doi:10.1523/JNEUROSCI.3883-03.2004. PMID 14715947. 

External links

• Achromatopsia at MedicineNet
• Achromatopsia at Merriam-Webster
• Achromatopsia at NCBI
• The Achromatopsia Network – an archive of information about Achromatopsia and advice on coping with the condition.

Classification	D ICD-11: 9B70, 9D44 ICD-10: H53.5 ICD-9-CM: 368.54 OMIM: 216900 MeSH: D003117 DiseasesDB: 83
External resources	MedlinePlus: 001002 GeneReviews: NBK1418 Medicine:GARD: ACHM Orphanet: 49382