Achromatopsia

Achromatopsia (ACHM) is the inability to see color. 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, also 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. There are at least four genetic causes of congenital ACHM, two of which are cyclic nucleotide-gated ion channels (ACHM2/ACHM3), a third the cone photoreceptor transducin (GNAT2, ACHM4), and the last unknown.

Additional recommended knowledge

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Classification

• Acquired achromatopsia (Cerebral achromatopsia)
• Congenital/inherited achromatopsia

• Complete/typical achrompatopsia (Rod monochromacy)
• Incomplete/atypical achromatopsia

Signs and symptoms

Complete Achromatopsia

Aside from a complete inability to discriminate colors, individuals with complete achromatopsia have a number of other opthalmologic aberrations. Included among these aberrations are greatly decreased visual acuity (<0.2 or 20/100), nystagmus, and severe photophobia. Furthermore, while the fundus is completely normal there is no photopic ERG response. Rod cell function is normal.

Incomplete Achromatopsia

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. Visual acuity and stability in this case improves during first 6-7 years of life.

Cause

Acquired Achromatopsia

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.

Congenital Achromatopsia

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 cells to properly respond to light input by hyperpolarizing. Known genetic causes of this are mutations in the cone cell cyclic nucleotide-gated ion channels CNGA3 (ACHM2) and CNGB3 (ACHM3) as well as the cone cell transducin, GNAT2 (ACHM4).

Pathophysiology

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 channels (CNGs). Decreasing the concentration of cGMP results in closure of CNGs and resulting hyperpolarization and cessation of glutamate release. Native retinal CNGs are comprised 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.

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 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.^[1] 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.^[2] 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.^[1]

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 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.^[6][7] 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.^[7] The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP.^[6][7] It is the increased affinity for cGMP and cAMP in these mutants that is likely the disease-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 of by light, rhodopsin 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, 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.

Epidemiology

Achromatopsia is a relatively common disorder, with a prevalence of 1 in 30,000 people.^[13] In the United States of America the disease afflict approximately 100,000 individuals.^[14] In the small Micronesian atoll of Pingelap approximately 5% of the atoll's 3000 inhabitant are afflicted.^[15][16]

Cultural references

In approximately 1775 Typhoon Lengkieki struck and devastated the Micronesian 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 "maksun", 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.^[16][17]

References

See also

• Monochromacy