Achromatopsia

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Achromatopsia
Classification and external resources
Grayscale 8bits palette sample image.png
A person with complete achromatopsia would see only black, white and shades of grey. Additionally, the image would usually be blurry in brighter light (in the brightest light, effectively invisible) but would be clear at very low lighting levels.
ICD-10 H53.5
ICD-9 368.54
OMIM 216900 262300 139340 613093
MeSH D003117

Achromatopsia (ACHM) 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 cerebral achromatopsia also known as color agnosia, 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 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 sun. 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.

Classification[edit]

  • Acquired achromatopsia (Cerebral achromatopsia)
  • 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.
  • Amblyopia–Defined conceptually by Duke-Elder (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. One form of lazy eye.
  • Hemeralopia–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 oscillation is quite noticeable and the frequency of the oscillation tends to be quite low.
  • Photophobia–The avoidance of bright light by those suffering from hemeralopia.

Signs and symptoms[edit]

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:

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 channels (ACHM2/ACHM3), a third involves the cone photoreceptor transducin (GNAT2, ACHM4), and the last remains unknown.

Complete achromatopsia[edit]

Aside from a complete inability to see color, individuals with complete achromatopsia have a number of other ophthalmologic 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.

Incomplete achromatopsia (dyschromatopsia)[edit]

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.

Cause[edit]

Acquired[edit]

Acquired achromatopsia/dyschromatopsia is a condition associated with damage to the diencephalon (primarily the thalamus 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.

Congenital[edit]

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).

A fourth genetic cause (ACHM5, OMIM 613093) has been discovered in 2009.[1] 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[edit]

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. 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 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.

ACHM2[edit]

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.[2] 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.[3] 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.[2]

Table 1. Summary of CNGA3 mutations found in achromatopsia patients
Mutation Region Functional?
(known or predicted)
Effect References
Nucleotide Amino acid
c.C67T p.R23X N-Term No? [4]
c.148insG p. I50DfsX59 N-Term No? [5]
c.A485T p.D162V N-Term [5]
c.C488T p.P163L N-Term ,[5][6]
c.A542G p.Y181C S1 No Does not properly traffic out of the endoplasmic reticulum ,[3][5]
c.A544T p.N182Y S1 No Does not properly traffic out of the endoplasmic reticulum ,[3][5]
c.C556T p. L186F S1 No Does not properly traffic out of the endoplasmic reticulum ,[3][5]
c.G572A p. C191Y S1-2 No Does not properly traffic out of the endoplasmic reticulum ,[3][5]
c.G580A p.E194K S1-2 No Does not properly traffic out of the endoplasmic reticulum [5]
c.C586T p.G196X S1-2 No? [4]
c.C661T p.R221X S2 No? [4]
c.C667T p.R223W S2-3 ,[4][5]
c.C671G p.T224R S2-3 No No current ,[2][5]
c.G778A p.D260N S3 [5]
c.G800A p.G267D S3-4 [5]
c.C829T p.R277C S4 [5]
c.G830A p.R277H S4 [5]
c.C847T p.R283Q S4 ,[5][6]
c.G848A p.R283W S4 ,[5][6]
c.C872G p.T291R S4 ,[5][6]
c.934_936del p. 312delI S5 [5]
c.G947A p.W316X S5 No? [5]
c.T1021C p.S341P Pore [5]
c.C1106G p.T369S pore Yes Increased calcium influx ,[2][5]
c.C1114T p.P372S Pore [5]
c.T1139C p.F380S Pore [5]
c.T1217C p.M406T S6 [5]
c.C1228T p.R410W C-term ,[5][6]
c.C1279T p.R427C C-term [5]
c.C1306T p.R436W C-term ,[4][5]
c.G1320A p.W440X C-term No? [5]
c.1350insG p. V451GfsX453 C-term No? [5]
c.A1412G p.N471S C-term [5]
c.1443insC p. I482HfsX5 C-term No? [4]
c.A1454T p.D485V C-term [5]
c.G1529C p. C510S cNMP [5]
c.G1538A p.G513E cNMP [5]
c.G1547A p.G516E cNMP [5]
c.T1565C p. I522T cNMP [5]
c.G1574A p.G525D cNMP [5]
c.G1585A p. V529M cNMP ,[5][6]
c.C1609T p.Q537X cNMP No? ,[4][5]
c.C1641A p.F547L cNMP ,[5][6]
c.G1642A p.G548R cNMP [4]
c.G1669A p.G557R cNMP ,[5][6]
c.G1688A p.R563H cNMP [5]
c.C1694T p.T565M cNMP [5]
c.G1706A p.R569H cNMP ,[4][5]
c.A1718G p.Y573C cNMP [5]
c.G1777A p.E593K cNMP [5]
c.C1963T p.Q655X C-term [5]
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[edit]

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.[7][8] 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.[8] The other mutations show either increased (S435F) or decreased (F525N) surface expression but also with increased affinity for cAMP and cGMP.[7][8] 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.

Table 2. Summary of CNGB3 mutations found in achromatopsia patients
Mutation Region Functional?
(known or predicted)
Effect References
Nucleotide Amino acid
c.29_30insA p.K10fsX9 N-Term No? [9]
c.C112T p.Q38X N-Term No? [9]
c.C391T p.Q131X N-Term No? [9]
c.A442G p.K148E N-Term [10]
c.446_447insT p.K149NfsX29 N-Term No? [10]
c.C467T p.S156F N-Term [9]
c.595delG p.E199SfsX2 N-Term No? [4]
c.C607T p.R203X N-Term No? ,[9][11]
c.G644-1C Splicing No? [9]
c.C646T p.R216X N-Term No? [9]
c.682_683insG p.A228GfsX2 S1 No? [9]
c.G702A p.W234X S1 No? [9]
c.706_707delinsTT p. I236FfsX25 S1 No? [9]
c.819_826del p.P273fsX13 S2-3 No? ,[11][12]
c.882_892delinsT p.R295QfsX9 S2-3 No? [9]
c.C926T p.P309L S3 [9]
c.T991-3G Splicing No? [9]
c.G1006T p.E336X S4 No? ,[9][11]
c.C1063T p.R355X S5 No? [9]
c.G1119A p.W373X S5 No? [9]
c.1148delC p.T383IfsX12 Pore No Does not traffic to the surface ,[4][7][8][9][11][12]
c.G1208A p.R403Q Pore Yes Increased outward rectification, increased cGMP affinity [8]
c.G1255T p.E419X Pore No? [9]
c.1298_1299del p. V433fsX27 S6 No? [9]
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 ,[7][9][11][12]
c.C1432T p.R478X C-term No? [9]
c.G1460A p.W487X C-term No? [9]
c.1573_1574delinsTT p.F525N C-term Yes Increased surface expression in oocytes, decreased outward rectification, increased cGMP and cAMP affinity ,[4][8]
c.G1578+1A Splicing No? ,[9][11]
c.T1635A p.Y545X cNMP No? [9]
c.G1781+1C Splicing No? [9]
c.G1781+1A Splicing No? [9]
c.2160_2180del p. 720_726del C-term [9]
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[edit]

Sensory rhodopsin II (rainbow colored) embedded in a lipid bilayer (heads red and tails blue) with Transducin below it. Gtα is colored red, Gtβ blue, and Gtγ yellow. There is a bound GDP molecule in the Gtα-subunit and a bound retinal (black) in the rhodopsin. The N-terminus terminus of rhodopsin is red and the C-terminus blue. Anchoring of transducin to the membrane has been drawn in black.

Upon activation 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.

Table 3. Summary of GNAT2 mutations found in achromatopsia patients
Mutation Functional?
(predicted)
References
Nucleotide Amino acid
c.C235T p.Q79X No? [13]
c.285_291del p.Y95fsX61 No? [13]
IVS3+365_IVS4+974del p.A101fsX12 No? [13]
c.503_504insT p. L168fsX3 No? [13]
c.802_803insTCAA p. L268fsX9 No? [13]
c.955del p. I319SfsX5 No? [13]

Management[edit]

There is generally no treatment to cure achromatopsia. However, since 2003, there is a cybernetic device called eyeborg that allows people to perceive color through sound waves.[14] 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 color.[15]

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.

Epidemiology[edit]

Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people (0.0033%).[16] However, in the small Micronesian atoll of Pingelap approximately 5% of the atoll's 3000 inhabitants are afflicted.[17][18]

Society and culture[edit]

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 "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.[18][19] Steppenwolf front man John Kay suffers from achromatopsia.

See also[edit]

References[edit]

  1. ^ Thiadens, A. A. H. J.; Den Hollander, A. I.; Roosing, S.; Nabuurs, S. B.; Zekveld-Vroon, R. C.; Collin, R. W. J.; De Baere, E.; Koenekoop, R. K.; Van Schooneveld, M. J.; Strom, T. M.; Van Lith-Verhoeven, J. J. C.; Lotery, A. J.; Van Moll-Ramirez, N.; Leroy, B. P.; Van Den Born, L. I.; Hoyng, C. B.; Cremers, F. P. M.; Klaver, C. C. W. (2009). "Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders". The American Journal of Human Genetics 85 (2): 240. doi:10.1016/j.ajhg.2009.06.016.  edit
  2. ^ a b c d Tränkner D, Jägle H, Kohl S, et al. (2004). "Molecular basis of an inherited form of incomplete achromatopsia". J. Neurosci. 24 (1): 138–47. doi:10.1523/JNEUROSCI.3883-03.2004. PMID 14715947. 
  3. ^ a b c d e Patel KA, Bartoli KM, Fandino RA, et al. (2005). "Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel". Invest. Ophthalmol. Vis. Sci. 46 (7): 2282–90. doi:10.1167/iovs.05-0179. PMID 15980212. 
  4. ^ a b c d e f g h i j k l Johnson S, Michaelides M, Aligianis IA, et al. (2004). "Achromatopsia caused by novel mutations in both CNGA3 and CNGB3". J. Med. Genet. 41 (2): e20. doi:10.1136/jmg.2003.011437. PMC 1735666. PMID 14757870. 
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at Wissinger B, Gamer D, Jägle H, et al. (2001). "CNGA3 mutations in hereditary cone photoreceptor disorders". Am. J. Hum. Genet. 69 (4): 722–37. doi:10.1086/323613. PMC 1226059. PMID 11536077. 
  6. ^ a b c d e f g h Kohl S, Marx T, Giddings I, et al. (1998). "Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel". Nat. Genet. 19 (3): 257–9. doi:10.1038/935. PMID 9662398. 
  7. ^ a b c d Peng C, Rich ED, Varnum MD (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): 34533–40. doi:10.1074/jbc.M305102200. PMID 12815043. 
  8. ^ a b c d e f Bright SR, Brown TE, Varnum MD (2005). "Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels". Mol. Vis. 11: 1141–50. PMID 16379026. 
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Kohl S, Varsanyi B, Antunes GA, et al. (2005). "CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia". Eur. J. Hum. Genet. 13 (3): 302–8. doi:10.1038/sj.ejhg.5201269. PMID 15657609. 
  10. ^ a b Rojas CV, María LS, Santos JL, Cortés F, Alliende MA (2002). "A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate". Eur. J. Hum. Genet. 10 (10): 638–42. doi:10.1038/sj.ejhg.5200856. PMID 12357335. 
  11. ^ a b c d e f Kohl S, Baumann B, Broghammer M, et al. (2000). "Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21". Hum. Mol. Genet. 9 (14): 2107–16. doi:10.1093/hmg/9.14.2107. PMID 10958649. 
  12. ^ a b c Sundin OH, Yang JM, Li Y, et al. (2000). "Genetic basis of total colourblindness among the Pingelapese islanders". Nat. Genet. 25 (3): 289–93. doi:10.1038/77162. PMID 10888875. 
  13. ^ a b c d e f Kohl S, Baumann B, Rosenberg T, et al. (2002). "Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia". Am. J. Hum. Genet. 71 (2): 422–5. doi:10.1086/341835. PMC 379175. PMID 12077706. 
  14. ^ Alfredo M. Ronchi: Eculture: Cultural Content in the Digital Age. Springer (New York, 2009). p.319 ISBN 978-3-540-75273-8
  15. ^ [1] The Sunday Times (UK, 2008)
  16. ^ Francois, J (1961). Heredity in ophthalmology. St. Louis: Mosby. 
  17. ^ Brody JA, Hussels I, Brink E, Torres J (1970). "Hereditary blindness among Pingelapese people of Eastern Caroline Islands". Lancet 1 (7659): 1253–7. doi:10.1016/S0140-6736(70)91740-X. PMID 4192495. 
  18. ^ a b Hussels IE, Morton NE (1972). "Pingelap and Mokil Atolls: achromatopsia". Am. J. Hum. Genet. 24 (3): 304–9. PMC 1762260. PMID 4555088. 
  19. ^ Sacks, Oliver (1997). The Island of the Colorblind. Picador. ISBN 0-330-35887-1. 

External links[edit]