Achromatopsia
Achromatopsia | |
---|---|
Other names | Rod Monochromacy |
Day blindness, Photophobia | |
Causes | Congenital malfunction of the Visual phototransduction pathway |
Diagnostic method | Electroretinography |
Frequency | 1/30,000 × 100% = 0.0033% |
Achromatopsia, also known as Rod monochromacy, is a medical syndrome that exhibits symptoms relating to five conditions, most notably
Signs and symptoms
The five symptoms associated with achromatopsia are:[citation needed]
- Color blindness – usually monochromacy
- Reduced visual acuity – uncorrectable with lenses
- Hemeralopia – with the subject exhibiting photophobia
- Nystagmus
- 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
Known genetic causes of this include mutations in the cone cell
Pathophysiology
This section may be too technical for most readers to understand.(October 2022) |
The hemeralopic aspect of achromatopsia can be diagnosed non-invasively using electroretinography. The response at low (
In general, the molecular pathomechanism of achromatopsia is either the inability to properly control or respond to altered levels of
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
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,
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:
- 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.[12]
- 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.[13]
- 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.[12]
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
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
Terminology
References
Footnotes
- S2CID 12040233.
- PMID 19615668.
- ^ a b Tränkner 2004, pp. 138–147.
- ^ Patel 2005, pp. 2282–2290.
- ^ a b Peng 2003, pp. 34533–34540.
- ^ a b c Bright 2005, pp. 1141–1150.
- PMID 35998912.
- S2CID 259504295.
- ^ Jackson, Justin; Xpress, Medical. "Gene therapy to restore color vision in complete achromatopsia patients shows modest improvement". medicalxpress.com. Retrieved 2023-08-28.
- ^ Ronchi 2009, p. 319.
- PMID 25926778.
- ^ a b Windsor, Richard; Windsor, Laura. "Driving Issues". achromatopsia.info. Retrieved 21 October 2022.
- ^ Corn 2010, p. 233.
- ^ Thiadens 2011, p. 59.
- ^ Brody 1970, pp. 1253–1257.
- ^ Hussels 1972, pp. 304–309.
- S2CID 22948732. Retrieved 18 August 2022.
- ^ Morton 1972, pp. 277–289.
- OCLC 473230128. Retrieved 18 August 2022.
- PMID 15858161.
- S2CID 5758683. Archived from the originalon 2013-01-28.
- PMID 2276043.
Sources
- Bright, S. R.; et al. (2005). "Disease-associated mutations in CNGB3 produce gain of function alterations in cone cyclic nucleotide-gated channels". PMID 16379026.
- Brody, J. A.; et al. (1970). "Hereditary blindness among Pingelapese people of Eastern Caroline Islands". PMID 4192495.
- Corn, A. N.; et al. (2010). Foundations of low vision: clinical and functional perspectives. Arlington: ISBN 9780891288831.
- Hussels, I. E.; et al. (1972). "Pingelap and Mokil Atolls: achromatopsia". PMID 4555088.
- Morton, N. E.; et al. (1972). "Pingelap and Mokil Atolls: historical genetics". PMID 4537352.
- Patel, K. A.; 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". PMID 15980212.
- Pearlman, E. (2015). "I, Cyborg". S2CID 57562971.
- Peng, C.; et al. (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". PMID 12815043.
- Ronchi, A. M. (2009). eCulture: cultural content in the digital age. Berlin: ISBN 9783540752738.
- Thiadens, A. A. H. J.; et al. (2009). "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders". PMID 19615668.
- Thiadens, A. A. H. J. (2011). Genetic etiology and clinical consequences of cone disorders. ISBN 9789461690579.
- Tränkner, D.; et al. (2004). "Molecular basis of an inherited form of incomplete achromatopsia". PMID 14715947.
External links
- Achromatopsia Archived 2020-02-23 at the Wayback Machine 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.