Achromatopsia

Last updated
Achromatopsia
Other namesRod Monochromacy
Specialty Ophthalmology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Monochromacy, Day blindness, Photophobia
CausesCongenital malfunction of the Visual phototransduction pathway
Diagnostic method Electroretinography
Frequency1/30,000× 100% = 0.0033%

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.

Contents

Signs and symptoms

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

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

The syndrome is typically first noticed in children around six months of age due to their photophobia 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. 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 ] The fundus of the eye appears completely normal.[ citation needed ]

Achromatopsia can be classified as complete or incomplete. 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 ]

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 at least four genetic causes of 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.[ citation needed ]

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 (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 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.[ 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 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.[ 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 ]

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.[ citation needed ]

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.[ citation needed ]

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.[ citation needed ]

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. [7] In July 2023, a study found positive but limited improvements on congenital CNGA3 achromatopsia. [8] [9]

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. [10] 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. [11]

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:

Epidemiology

Achromatopsia is a relatively uncommon disorder, with a prevalence of 1 in 30,000 people. [14]

However, on the small Micronesian atoll of Pingelap, approximately five percent of the atoll's 3,000 inhabitants are affected. [15] [16] 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. [17]

The people of this region have termed achromatopsia "maskun", which literally means "not see" in Pingelapese. [18] This unusual population drew neurologist Oliver Sacks to the island for which he wrote his 1997 book, The Island of the Colorblind . [19]

Blue cone monochromacy

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 as x-linked achromatopsia, sex-linked achromatopsia or atypical achromatopsia. BCM stems from mutations or deletions of the OPN1LW and OPN1MW genes, both on the X chromosome. As a recessive x-linked condition, BCM disproportionately affects males, unlike typical achromatopsia.[ citation needed ]

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.[ citation needed ] It is most frequently caused by physical trauma, hemorrhage or tumor tissue growth. [20] If there is unilateral damage, a loss of color perception in only half of the visual field may result; this is known as hemiachromatopsia. [21] Cerebral achromats usually do not experience the other major symptoms of congenital achromatopsia, since photopic vision is 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. [22]

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

Related Research Articles

<span class="mw-page-title-main">Retinitis pigmentosa</span> Gradual retinal degeneration leading to progressive sight loss

Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Transducin</span>

Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors.

<span class="mw-page-title-main">Rod cell</span> Photoreceptor cells that can function in lower light better than cone cells

Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 92 million rod cells in the human retina. Rod cells are more sensitive than cone cells and are almost entirely responsible for night vision. However, rods have little role in color vision, which is the main reason why colors are much less apparent in dim light.

<span class="mw-page-title-main">Guanylate cyclase</span> Lyase enzyme that synthesizes cGMP from GTP

Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:

<span class="mw-page-title-main">Monochromacy</span> Type of color vision

Monochromacy is the ability of organisms to perceive only light intensity without respect to spectral composition. Organisms with monochromacy lack color vision and can only see in shades of grey ranging from black to white. Organisms with monochromacy are called monochromats. Many mammals, such as cetaceans, the owl monkey and the Australian sea lion are monochromats. In humans, monochromacy is one among several other symptoms of severe inherited or acquired diseases, including achromatopsia or blue cone monochromacy, together affecting about 1 in 30,000 people.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

Visual phototransduction is the sensory transduction process of the visual system by which light is detected by photoreceptor cells in the vertebrate retina. A photon is absorbed by a retinal chromophore, which initiates a signal cascade through several intermediate cells, then through the retinal ganglion cells (RGCs) comprising the optic nerve.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span> Class of enzymes

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

<span class="mw-page-title-main">PDE6B</span> Protein-coding gene in the species Homo sapiens

Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta is the beta subunit of the protein complex PDE6 that is encoded by the PDE6B gene. PDE6 is crucial in transmission and amplification of visual signal. The existence of this beta subunit is essential for normal PDE6 functioning. Mutations in this subunit are responsible for retinal degeneration such as retinitis pigmentosa or congenital stationary night blindness.

<span class="mw-page-title-main">Cyclic nucleotide-gated channel alpha 3</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide-gated cation channel alpha-3 is a protein that in humans is encoded by the CNGA3 gene.

<span class="mw-page-title-main">GNAT2</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(t) subunit alpha-2 is a protein that in humans is encoded by the GNAT2 gene.

<span class="mw-page-title-main">Cyclic nucleotide gated channel beta 3</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide gated channel beta 3, also known as CNGB3, is a human gene encoding an ion channel protein.

<span class="mw-page-title-main">Cyclic nucleotide-gated channel alpha 1</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide-gated channel alpha 1, also known as CNGA1, is a human gene encoding an ion channel protein. Heterologously expressed CNGA1 can form a functional channel that is permeable to calcium. In rod photoreceptors, however, CNGA1 forms a heterotetramer with CNGB1 in a 3:1 ratio. The addition of the CNGB1 channel imparts altered properties including more rapid channel kinetics and greater cAMP-activated current. When light hits rod photoreceptors, cGMP concentrations decrease causing rapid closure of CNGA1/B1 channels and, therefore, hyperpolarization of the membrane potential.

<span class="mw-page-title-main">CNGB1</span> Protein-coding gene in the species Homo sapiens

Cyclic nucleotide gated channel beta 1, also known as CNGB1, is a human gene encoding an ion channel protein.

<span class="mw-page-title-main">PDE6C</span> Protein-coding gene in the species Homo sapiens

Cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha' is an enzyme that in humans is encoded by the PDE6C gene.

<span class="mw-page-title-main">Cyclic nucleotide-binding domain</span>

Proteins that bind cyclic nucleotides share a structural domain of about 120 residues. The best studied of these proteins is the prokaryotic catabolite gene activator where such a domain is known to be composed of three alpha-helices and a distinctive eight-stranded, antiparallel beta-barrel structure. There are six invariant amino acids in this domain, three of which are glycine residues that are thought to be essential for maintenance of the structural integrity of the beta-barrel. cAMP- and cGMP-dependent protein kinases contain two tandem copies of the cyclic nucleotide-binding domain. The cAPK's are composed of two different subunits, a catalytic chain and a regulatory chain, which contains both copies of the domain. The cGPK's are single chain enzymes that include the two copies of the domain in their N-terminal section. Vertebrate cyclic nucleotide-gated ion-channels also contain this domain. Two such cations channels have been fully characterized, one is found in rod cells where it plays a role in visual signal transduction.

Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.

Blue cone monochromacy (BCM) is an inherited eye disease that causes severe color blindness, poor visual acuity, nystagmus, hemeralopia, and photophobia due to the absence of functional red (L) and green (M) cone photoreceptor cells in the retina. BCM is a recessive X-linked disease and almost exclusively affects XY karyotypes.

<span class="mw-page-title-main">Retinal cone dystrophy 3B</span> Medical condition

Retinal cone dystrophy 3B is a very rare genetic disorder which is characterized by ocular anomalies. Approximately 34 cases from 20 families across the world have been described in medical literature (OMIM). This disorder is associated with autosomal recessive mutations in the KCNV2 and PDE6H genes.

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, Dimitri; Jägle, Herbert; Kohl, Susanne; Apfelstedt-Sylla, Eckart; Sharpe, Lindsay T.; Kaupp, U. Benjamin; Zrenner, Eberhart; Seifert, Reinhard; Wissinger, Bernd (2004-01-07). "Molecular Basis of an Inherited Form of Incomplete Achromatopsia". The Journal of Neuroscience. 24 (1): 138–147. doi:10.1523/JNEUROSCI.3883-03.2004. ISSN   0270-6474. PMC   6729583 . PMID   14715947.
  4. Patel, Kirti A.; Bartoli, Kristen M.; Fandino, Richard A.; Ngatchou, Anita N.; Woch, Gustaw; Carey, Jannette; Tanaka, Jacqueline C. (2005-07-01). "Transmembrane S1 Mutations in CNGA3 from Achromatopsia 2 Patients Cause Loss of Function and Impaired Cellular Trafficking of the Cone CNG Channel". Investigative Ophthalmology & Visual Science. 46 (7): 2282–2290. doi:10.1167/iovs.05-0179. ISSN   1552-5783. PMID   15980212.
  5. 1 2 Peng, Changhong; Rich, Elizabeth D.; Varnum, Michael D. (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". Journal of Biological Chemistry. 278 (36): 34533–34540. doi: 10.1074/jbc.M305102200 . PMID   12815043.
  6. 1 2 3 Bright 2005, pp. 1141–1150.
  7. Farahbakhsh, Mahtab; Anderson, Elaine J; Maimon-Mor, Roni O; Rider, Andy; Greenwood, John A; Hirji, Nashila; Zaman, Serena; Jones, Pete R; Schwarzkopf, D Samuel; Rees, Geraint; Michaelides, Michel; Dekker, Tessa M (24 August 2022). "A demonstration of cone function plasticity after gene therapy in achromatopsia". Brain. 145 (11): 3803–3815. doi:10.1093/brain/awac226. PMC   9679164 . PMID   35998912.
  8. McKyton, Ayelet; Marks Ohana, Devora; Nahmany, Einav; Banin, Eyal; Levin, Netta (July 2023). "Seeing color following gene augmentation therapy in achromatopsia". Current Biology. 33 (16): 3489–3494.e2. Bibcode:2023CBio...33E3489M. doi:10.1016/j.cub.2023.06.041. PMID   37433300. S2CID   259504295.
  9. Jackson, Justin; Xpress, Medical. "Gene therapy to restore color vision in complete achromatopsia patients shows modest improvement". medicalxpress.com. Retrieved 2023-08-28.
  10. Ronchi, Alfredo M. (2009). eCulture. Berlin, Heidelberg: Springer Berlin Heidelberg. doi:10.1007/978-3-540-75276-9. ISBN   978-3-540-75273-8.
  11. Alfaro, Arantxa; Bernabeu, Ángela; Agulló, Carlos; Parra, Jaime; Fernández, Eduardo (14 April 2015). "Hearing colors: an example of brain plasticity". Frontiers in Systems Neuroscience. 9: 56. doi: 10.3389/fnsys.2015.00056 . PMC   4396351 . PMID   25926778.
  12. 1 2 Windsor, Richard; Windsor, Laura. "Driving Issues". achromatopsia.info. Retrieved 21 October 2022.
  13. Corn 2010, p. 233.
  14. Thiadens, Alberta A.H.J.; Phan, T. My Lan; Zekveld-Vroon, Renate C.; Leroy, Bart P.; van den Born, L. Ingeborgh; Hoyng, Carel B.; Klaver, Caroline C.W.; Roosing, Susanne; Pott, Jan-Willem R.; van Schooneveld, Mary J.; van Moll-Ramirez, Norka; van Genderen, Maria M.; Boon, Camiel J.F.; den Hollander, Anneke I.; Bergen, Arthur A.B. (2012). "Clinical Course, Genetic Etiology, and Visual Outcome in Cone and Cone–Rod Dystrophy". Ophthalmology. 119 (4): 819–826. doi:10.1016/j.ophtha.2011.10.011. PMID   22264887.
  15. Brody, Jacob A.; Hussels, Irena; Brink, Edward; Torres, Jose (1970). "Hereditary blindness among Pingelapese people of Eastern Caroline Islands". The Lancet. 295 (7659): 1253–1257. doi:10.1016/S0140-6736(70)91740-X.
  16. Hussels 1972, pp. 304–309.
  17. Sundin, Olof H.; Yang, Jun-Ming; Li, Yingying; Zhu, Danping; Hurd, Jane N.; Mitchell, Thomas N.; Silva, Eduardo D.; Maumenee, Irene Hussels (2000). "Genetic basis of total colourblindness among the Pingelapese islanders". Nature Genetics. 25 (3): 289–293. doi:10.1038/77162. PMID   10888875. S2CID   22948732 . Retrieved 18 August 2022.
  18. Morton 1972, pp. 277–289.
  19. Sacks, Oliver W. (1997). The island of the colorblind; and Cycad island. New York: A.A. Knopf. OCLC   473230128 . Retrieved 18 August 2022.
  20. Bouvier, Seth E.; Engel, Stephen A. (2006-02-01). "Behavioral Deficits and Cortical Damage Loci in Cerebral Achromatopsia". Cerebral Cortex. 16 (2): 183–191. doi:10.1093/cercor/bhi096. ISSN   1460-2199. PMID   15858161.
  21. Burns, Martha S. (2004). "Clinical Management of Agnosia". Topics in Stroke Rehabilitation. 11 (1): 1–9. doi:10.1310/N13K-YKYQ-3XX1-NFAV. ISSN   1074-9357. PMID   14872395.
  22. Zeki, Semir (1990). "A century of cerebral achromatopsia". Brain. 113 (6): 1721–1777. doi:10.1093/brain/113.6.1721. ISSN   0006-8950. PMID   2276043.

Sources