Achromatopsia

Achromatopsia
Known as
Total color blindness
SymptomsDay blindness, involuntary eye movement, lazy eye, photophobia
Causes
Frequency1/30,000 × 100% = 0.00333333333333%

Achromatopsia, also known as total color blindness, is a medical syndrome that exhibits symptoms relating to at least five conditions. The term may refer to acquired conditions such as cerebral achromatopsia, but it typically refers to an autosomal recessive congenital color vision condition, the inability to perceive color and to obtain 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. It is estimated to affect 1 in 30,000 live births worldwide.

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 five 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 sunlight. In patients with achromatopsia, the cone system and fibres carrying color information remain intact. This indicates that the mechanism used to construct colors is defective.

Signs and symptoms

The syndrome is frequently noticed first in children around six months of age by their photophobic activity 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. The congenital forms of the condition are considered stationary and do not worsen with age.

The five symptoms associated with achromatopsia or dyschromatopsia are:

  1. Achromatopsia
  2. Amblyopia – reduced visual acuity
  3. Hemeralopia – with the subject exhibiting photophobia
  4. Nystagmus
  5. Iris operating abnormalities

The syndrome of achromatopsia or dyschromatopsia is poorly described in current medical and neuro-ophthalmological texts. It became a common term following the release of neuroscientist Oliver Sacks' book, 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 condition show complete absence of cone cell activity via electroretinography at high light levels. There are at least four genetic causes of congenital 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.

Complete achromatopsia

Aside from a complete inability to see color, individuals with complete achromatopsia have a number of other ophthalmologic aberrations. Included among these optical aberrations are greatly decreased visual acuity (<0.1 or 20 in daylight, hemeralopia, nystagmus, and severe photophobia). The fundus of the eye appears completely normal.

Incomplete achromatopsia

In general, symptoms of incomplete achromatopsia (dyschromatopsia) 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.

Cause

Acquired

Acquired achromatopsia or dyschromatopsia is a condition associated with damage to the diencephalon—primarily the thalamus of the mid brain—or the cerebral cortex—the new brain—specifically the fourth visual association area, V4 which receives information from the parvocellular pathway involved in color processing.

Thalamic achromatopsia or 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.

Congenital

The known causes of the congenital forms of achromatopsia are due to malfunction of the retinal phototransduction pathway. Specifically, this form of achromatopsia seems to result from the inability of cone cells to properly respond to light input by hyperpolarizing. Known genetic causes of this include mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2)[1] and CNGB3 (ACHM3), the cone cell transducin, GNAT2 (ACHM4), subunits of cone phosphodiesterase PDE6C (ACHM5, OMIM 613093)[2] and PDEH (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 (mesotopic) light levels will be normal but the response under high light level (photopic) conditions will be absent. The mesotopic 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; particularly important in visual perception 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 release.Native retinal CNGs are composed of 2 α- and 2 β-subunits, which are CNGA3 and CNGB3, respectively, in cone 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+ 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 photons. There is a positive correlation between the severity of mutations in these proteins and the completeness of the achromatopsia phenotype.

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 permeability.

When mutant T369S channels coassemble with CNGB3, however, the only remaining aberration is increased calcium permeability.[3] 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.[4] 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.[3]

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.[5][6]

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.[6] The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP.[5][6] 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) 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 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, 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.

Diagnosis

OCT image from a normal subject left and an achromatopsia individual right

The diagnosis for this ocular condition is based on the following:[7]

  • Color vision test
  • ERG
  • OCT
  • Fundus autofluorescence image

Management

There is generally no treatment to cure achromatopsia. However, dark red or plum colored filters are very helpful in controlling light sensitivity.[8] Since 2003, there is a cybernetic device called eyeborg that allows people to perceive color through sound waves.[9] Achromatopsic artist Neil Harbisson was the first to use such a device in early 2004, the eyeborg allowed him to start painting in color by memorizing the sound of each color.[10] 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, phase 1 trials are starting. There are many challenges to conducting gene therapy for color blindness on humans.

Epidemiology

Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people.[11]

However, on the small Micronesian atoll of Pingelap, approximately five percent of the atoll's 3,000 inhabitants are affected.[12][13] 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.[14] This unusual population drew neurologist Oliver Sacks to the island for which he wrote his 1997 book, The Island of the Colorblind.

Terminology

Acquired achromatopsia
Cerebral achromatopsia
Congenital or inherited achromatopsia
1.  Complete typical achromatopsia
2.  Incomplete atypical achromatopsia, or incomplete atypical dyschromatopsia
Achromatopsia
Complete lack of the perception of color in a subject, seeing only in black, white, and shades of grey. This is different from color agnosia, in which a person can perceive color—as measured by a matching task—but cannot recognize different colors.
Amblyopia
Defined conceptually by Sir Stewart Duke-Elder in 1973 as a monocular acuity deficit which is not due to refractive error or any organic abnormality.[15] Poor spatial performance of the precision optical servomechanism of the eyes at nominal illumination levels without any morphological cause. One form of lazy eye.
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.

References

Footnotes

  1. ↑ Kohl, Susanne; Marx, Tim; Giddings, Ian; Jägle, Herbert; Jacobson, Samuel G.; Apfelstedt-Sylla, Eckhart; Zrenner, Eberhart; Sharpe, Lindsay T.; Wissinger, Bernd (July 1998). "Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel". Nature Genetics. 19 (3): 257–259. doi:10.1038/935. PMID 9662398. S2CID 12040233.
  2. ↑ Thiadens, Alberta A.H.J.; den Hollander, Anneke I.; Roosing, Susanne; Nabuurs, Sander B.; Zekveld-Vroon, Renate C.; Collin, Rob W.J.; De Baere, Elfride; Koenekoop, Robert K.; van Schooneveld, Mary J.; Strom, Tim M.; van Lith-Verhoeven, Janneke J.C.; Lotery, Andrew J.; van Moll-Ramirez, Norka; Leroy, Bart P.; van den Born, L. Ingeborgh; Hoyng, Carel B.; Cremers, Frans P.M.; Klaver, Caroline C.W. (August 2009). "Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders". The American Journal of Human Genetics. 85 (2): 240–247. doi:10.1016/j.ajhg.2009.06.016. PMC 2725240. PMID 19615668.
  3. 1 2 Tränkner 2004, pp. 138–147.
  4. ↑ Patel 2005, pp. 2282–2290.
  5. 1 2 Peng 2003, pp. 34533–34540.
  6. 1 2 3 Bright 2005, pp. 1141–1150.
  7. ↑ Kohl, Susanne; Jägle, Herbert; Wissinger, Bernd; Zobor, Ditta (1993). "Achromatopsia". GeneReviews®. University of Washington, Seattle. Archived from the original on 1 August 2019. Retrieved 22 July 2022.
  8. ↑ Corn 2010, p. 233.
  9. ↑ Ronchi 2009, p. 319.
  10. ↑ Pearlman 2015, pp. 84–90.
  11. ↑ Thiadens 2011, p. 59.
  12. ↑ Brody 1970, pp. 1253–1257.
  13. ↑ Hussels 1972, pp. 304–309.
  14. ↑ Morton 1972, pp. 277–289.
  15. ↑ Duke-Elder 1976.

Sources

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