Medicine:Blue-cone monochromacy

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Blue cone monochromacy
Other namesX-linked achromatopsia
Symptomspoor ability or inability to distinguish colours, poor visual acuity, nystagmus, hemeralopia
Usual onsetcongenital
Differential diagnosisincomplete achromatopsia
Treatmentdark lenses
Frequency1 in 100,000

Blue cone monochromacy (BCM) is an inherited eye disease that causes severe color blindness, poor visual acuity, nystagmus 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.


Cone cells are one kind of photoreceptor cell in the retina that are responsible for the photopic visual system and mediate color vision. The cones are categorized according to their spectral sensitivity:

  • LWS (long wave sensitive) cones are most sensitive to red light.
  • MWS (middle wave sensitive) cones are most sensitive to green light.
  • SWS (short wave sensitive) cones are most sensitive to blue light.

MWS and LWS cones are most responsible for visual acuity as they are concentrated in the fovea centralis region of the retina, which constitutes the very center of the visual field. Blue cone monochromacy is a severe condition in which the cones sensitive to red or green light are missing or defective, and only S-cones sensitive to blue light and rods which are responsible for night (scotopic) vision are functional.[1][2]


A variety of symptoms characterize BCM:[2][3]

BCM symptoms are usually stationary, but some studies show evidence of disease progression.[4]

Poor Color Discrimination

The color vision of Blue cone monochromats is severely impaired. However, interaction of the blue cones and rod photoreceptors in mesopic vision (twilight) may enable some level of dichromacy.[5]



Because Blue cone monochromacy shares many symptoms with achromatopsia, it was historically treated as a subset of achromatopsia, called x-linked achromatopsia or atypical incomplete achromatopsia. Both of these names differentiated BCM specifically by how its inheritance pattern deviated from other forms of achromatopsia. While other forms (ACHM) follow autosomal inheritance, BCM is X-Linked. Once the molecular biological basis of BCM was understood, the more descriptive term Blue cone monochromacy became dominant in the literature.


The gene cluster responsible for BCM comprises 3 genes and is located at position Xq28, at the end of the q arm of the X chromosome.[6] The genes in the cluster are summarized in the following table:

Type OMIM Gene Locus Purpose
Locus Control Region Online Mendelian Inheritance in Man (OMIM) 300824 LCR[1] Xq28 Acts as a promoter of the expression of the two opsin genes thereafter,[1] and ensures that only one of the two opsins (LWS or MWS) is expressed exclusively in each cone.[7]
LWS opsin Online Mendelian Inheritance in Man (OMIM) 300822 OPN1LW Xq28 Encodes the LWS (red) photopsin protein.
MWS opsin Online Mendelian Inheritance in Man (OMIM) 300821 OPN1MW Xq28 Encodes the MWS (green) photopsin protein.

Originating from a recent duplication event, the two opsins are highly homologous (very similar), having only 19 dimorphic sites (amino acids that differ),[8] and are therefore 96% similar.[9] Furthermore, only 7 of these dimorphic sites lead to a functional difference between the genes, i.e. that tune the opsin's spectral sensitivity. In comparison, these opsin genes are only 40% homologous (similar) to OPN1SW (encoding the SWS photopsin and located on chromosome 7) and "RHO" (encoding rhodopsin, and located on chromosome 3).[9] OPN1SW and rhodopsin are unaffected in BCM.


Since BCM is caused by non-functional M- and L-cones, it can result from the intersection of protanopia (no functional L-cones) and deuteranopia (no functional M-cones). Therefore the genetic causes of BCM include the genetic causes of protanopia and deuteranopia. These include (affecting either opsin gene):[9]

  • deletions of the opsin genes, often from nonhomologous recombination.
  • point mutations that lead to non-functional (inactivated) opsins:
  • intragenic deletion of whole exon 4[9][11]
  • LIAVA genotype: inactivation through homologous recombination that ends with Exon 3 of the hybrid opsin gene containing the following amino acids in the positions indicated: 153 Leucine, 171 Isoleucine, 174 Alanine, 178 Valine and 180 Alanine.[7]

Data from the BCM International Patient Registry [12] shows that about 35% of Blue cone monochromacy stems from this 2-step process, where both genes are each affected by one of the above mutations.[9] The remaining 55% of Blue cone monochromats are caused by a deletion of the LCR.[9] In the absence of LCR, neither of the following two opsin genes are expressed.

Another disease of the retina that is associated with the position Xq28 is Bornholm Eye Disease (BED).[7] The point mutation W177R is a missense mutation that causes cone dystrophy when present on both opsin genes.[3]


Children 2 months and older can be identified as possible Blue cone monochromats from observing an aversion to light and/or nystagmus,[13] but are not sufficient for diagnosis, and especially not the differential diagnosis with achromatopsia. The differential diagnosis can be achieved in a few ways:

  • through reconstructing the family history to establish a x-linked mode of heredity[14][2][4]
  • with an electroretinogram (ERG), which measures the electrical response of photoreceptors to a visual stimulus of known wavelength. This can demonstrate the loss of function of the LWS and MWS cones.[15]
  • with a color vision test, either general in nature like the Farnsworth D-15[4] or Farnsworth Munsell 100 Hue test[15] or the Berson test, which is specifically designed to differentiate BCM from typical achromatopsia.[16]


Corrective visual aides and personalized vision therapy provided by Low Vision Specialists may help patients correct glare and optimize their remaining visual acuity. Tinted lenses for photophobia allow for greater visual comfort. A magenta (mixture of red and blue) tint allows for best visual acuity since it protects the rods from saturation while allowing the blue cones to be maximally stimulated.

Gene therapy

Main page: Biology:Gene therapy for color blindness

There is no cure for Blue cone monochromacy; however, the efficacy and safety of prospective treatments are currently being evaluated, namely Gene therapy. Gene therapy is a general treatment for genetic disorders. It uses viral vectors to carry typical genes into cells (e.g. cone cells) that are not able to express functional genes (e.g. photopsins). By adding missing opsin genes, or a functional copy of the entire gene complex into the cone cells, color vision may be able to be restored. In 2015, a team at the University of Pennsylvania evaluated possible outcoming measures of BCM gene therapy[17] Since 2011, several studies have performed gene therapy for blue cone monochromacy on mouse and rat models,[18] but there have been no clinical trials (on humans) and as of October 2022, none are publicly planned according to


BCM affects approximately 1/100,000 individuals.[14] The disease affects males much more than females due to its recessive X-linked nature, while females usually remain unaffected carriers of the BCM trait.[6]


Prior to the 1960s, Blue cone monochromacy was treated as a subset of achromatopsia. The first detailed description of achromatopsia was given in 1777, where the subject of the description:

...could never do more than guess the name of any color; yet he could distinguish white from black, or black from any light or bright color...He had 2 brothers in the same circumstances as to sight; and 2 brothers and sisters who, as well as his parents, had nothing of this defect.

In 1942, Sloan first distinguished typical and atypical achromatopsia, differentiated mainly on the inheritance patterns.[19] In 1953, Weale theorized that the atypical achromatopsia must stem from cone-monochromatism, but estimated a prevalence of only 1 in 100 million.[20] In the early 1960's, the inheritance of atypical achromatopsia led to a name change to x-linked achromatopsia, and at the same time, several studies demonstrated that Blue cone monochromats retain some Blue yellow color vision.[21][22] A significant discovery was announced in 1989 (and 1993) by Nathans et al.[1][2] who identified the genes causing Blue cone monochromacy.


  1. 1.0 1.1 1.2 1.3 Nathans, J; Davenport, C M; Maumenee, I H; Lewis, R A; Hejtmancik, J F; Litt, M; Lovrien, E; Weleber, R et al. (1989). "Molecular genetics of human blue cone monochromacy". Science 245 (4920): 831–838. doi:10.1126/science.2788922. PMID 2788922. Bibcode1989Sci...245..831N. 
  2. 2.0 2.1 2.2 2.3 Nathans, J; Maumenee, I H; Zrenner, E; Sadowski, B; Sharpe, L T; Lewis, R A; Hansen, E; Rosenberg, T et al. (1993). "Genetic heterogeneity among blue cone monochromats". Am. J. Hum. Genet. 53 (5): 987–1000. PMID 8213841. 
  3. 3.0 3.1 Gardner, J C; Webb, T R; Kanuga, N; Robson, A G; Holder, G E; Stockman, A; Ripamonti, C; Ebenezer, N D et al. (2010). "X-Linked Cone Dystrophy Caused by Mutation of the Red and Green Cone Opsins". Am. J. Hum. Genet. 87 (1): 26–39. doi:10.1016/j.ajhg.2010.05.019. PMID 20579627. 
  4. 4.0 4.1 4.2 Michaelides, M; Johnson, S; Simunovic, M P; Bradshaw, K; Holder, G; Mollon, J D; Moore, A T; Hunt, D M (2005). "Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals". Eye (Lond) 19 (1): 2–10. doi:10.1038/sj.eye.6701391. PMID 15094734. 
  5. Reitner, A; Sharpe, L T; Zrenner, E (1991). "Is colour vision possible with only rods and Blue sensitive cones?". Nature 352 (6338): 798–800. doi:10.1038/352798a0. PMID 1881435. Bibcode1991Natur.352..798R. 
  6. 6.0 6.1 "Colour vision in blue cone 'monochromacy'". J. Physiol. 212 (1): 211–33. January 1971. doi:10.1113/jphysiol.1971.sp009318. PMID 5313219. 
  7. 7.0 7.1 7.2 Neitz, J; Neitz, M (2011). "The genetics of normal and defective color vision". Vision Res. 51 (7): 633–651. doi:10.1016/j.visres.2010.12.002. PMID 21167193. 
  8. Neitz, Maureen (1 May 2000). "Molecular Genetics of Color Vision and Color Vision Defects". Archives of Ophthalmology 118 (5): 691–700. doi:10.1001/archopht.118.5.691. PMID 10815162. 
  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 Gardner, Jessica C.; Michaelides, Michel; Holder, Graham E.; Kanuga, Naheed; Webb, Tom R.; Mollon, John D.; Moore, Anthony T.; Hardcastle, Alison J. (1 May 2009). "Blue cone monochromacy: Causative mutations and associated phenotypes". Molecular Vision 15: 876–884. ISSN 1090-0535. PMID 19421413. 
  10. "Defective colour vision associated with a missense mutation in the human green visual pigment gene". Nat. Genet. 1 (4): 251–6. July 1992. doi:10.1038/ng0792-251. PMID 1302020. 
  11. Ladekjaer-Mikkelsen, A S; Rosenberg, T; Jørgensen, A L (1996). "A new mechanism in blue cone monochromatism". Hum. Genet. 98 (4): 403–408. doi:10.1007/s004390050229. PMID 8792812. 
  12. "Patient Registry – Blue Cone Monochromacy". 
  13. Alpern, M; Falls, H F; Lee, G B (1960). "The enigma of typical total monochromacy". Am. J. Ophthalmol. 50 (5): 996–1012. doi:10.1016/0002-9394(60)90353-6. PMID 13682677. 
  14. 14.0 14.1 Kohl, S; Hamel, C P (2011). "Clinical utility gene card for: blue cone monochromatism". Eur. J. Hum. Genet. 19 (6): 732. doi:10.1038/ejhg.2010.232. PMID 21267011. 
  15. 15.0 15.1 Ayyagari, R; Kakuk, L E; Bingham, E L; Szczesny, J J; Kemp, J; Toda, Y; Felius, J; Sieving, P A (2000). "Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy". Hum. Genet. 107 (1): 75–82. doi:10.1007/s004390000338. PMID 10982039. 
  16. "Color plates to help identify patients with blue cone monochromatism". Am. J. Ophthalmol. 95 (6): 741–7. June 1983. doi:10.1016/0002-9394(83)90058-2. PMID 6602551. 
  17. Luo, X; Cideciyan, AV; Iannaccone, A; Roman, A J; Ditta, L C; Jennings, B J; Yatsenko, S; Sheplock, R et al. (2015). "Blue cone monochromacy: visual function and efficacy outcome measures for clinical trials". PLOS ONE 10 (4): e0125700. doi:10.1371/journal.pone.0125700. PMID 25909963. Bibcode2015PLoSO..1025700L. 
  18. Zhang, Y; Deng, WT; Du, W; Zhu, P; Li, J; Xu, F; Sun, J; Gerstner, C D et al. (2017). "Gene-based Therapy in a Mouse Model of Blue Cone Monochromacy". Scientific Reports 7 (6690): 6690. doi:10.1038/s41598-017-06982-7. PMID 28751656. Bibcode2017NatSR...7.6690Z. 
  19. Sloan, LL; Newhall, SM (1942). "Comparison of cases of atypical and typical achromatopsia". American Journal of Ophthalmology 25 (8): 945–961. doi:10.1016/S0002-9394(42)90594-4. 
  20. Weale, RA (1953). "Cone Monochromatism". The Journal of Physiology 121 (3): 548–569. doi:10.1113/jphysiol.1953.sp004964. PMID 13097391. 
  21. Blackwell, H R; Blackwell, O M (1961). "Rod and cone receptor mechanisms in typical and atypical congenital achromatopsia". Vision Res. 1 (1–2): 62–107. doi:10.1016/0042-6989(61)90022-0. 
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