Blue cone monochromacy

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 males.

Blue cone monochromacy
Other namesX-linked achromatopsia
SpecialtyOphthalmology
SymptomsMonochromacy, poor visual acuity, nystagmus, hemeralopia
Usual onsetcongenital
Differential diagnosisincomplete achromatopsia
Treatmentdark lenses
Frequency1 in 100,000

Cause

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]

Red cone monochromacy and green cone monochromacy are believed to exist, but a clinical case has not yet been differentially diagnosed from blue cone monochromacy. The group of disorders are collectively referred to as cone monochromacy (as opposed to rod monochromacy), but this term is usually treated as synonymous with blue cone monochromacy.

Symptoms

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

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

Monochromacy

The color vision of blue cone monochromats is generally described as monochromacy or total color blindness. However, interaction of the blue cones and rod photoreceptors in mesopic vision (twilight) may enable some level of dichromacy.[5]

Genetics

Heredity

Because blue cone monochromacy shares many symptoms with the syndrome achromatopsia, it was historically treated as a subset of achromatopsia, called x-linked achromatopsia or atyical 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 sex-linked). Once the molecular biological basis of BCM was understood, the more descriptive term blue cone monochromacy became dominant in the literature.

Genes

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:

TypeOMIMGeneLocusPurpose
Locus Control Region 300824LCR[1]Xq28Acts 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 300822OPN1LWXq28Encodes the LWS (red) photopsin protein.
MWS opsin 300821OPN1MWXq28Encodes 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.

Mutations

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:
    • C203R: a missense mutation.[9][10]
    • P307L[9]
    • R247X: a nonsense mutation.[9]
  • 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]

About 60% of blue cone monochromacy stems from this 2-step process, where both genes are each affected by one of the above mutations.[9] The majority of these (about 50% of the total) have a deletion of the L-opsin (by itself causing protanopia) mixed with a C203R mutation of the M-opsin (by itself causing deuteranopia).[2] The remaining 40% 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]

Diagnosis

Children 2 months and older can be identified as possible blue cone monochromats from observing an aversion to light and/or nystagmus,[12] 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[13][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.[14]
  • with a color vision test, either general in nature like the Farnsworth D-15[4] or Farnsworth Munsell 100 Hue test[14] or the Berson test, which is specifically designed to differentiate BCM from typical achromatopsia.[15]

Treatment

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 article: 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[16] Since 2011, several studies have performed gene therapy for blue cone monochromacy on mouse and rat models,[17] but there have been no clinical trials (on humans) and as of October 2022, none are publicly planned according to ClinicalTrials.gov

Epidemiology

BCM affects approximately 1/100,000 individuals.[13] 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]

History

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.

— J. Huddart, "Article Title", An account of persons who could not distinguish colours (1777)[18]

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.

References
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  2. Nathans, J; Maumenee, I H; Zrenner, E; Sadowski, B; Sharpe, L T; Lewis, R A; Hansen, E; Rosenberg, T; Schwartz, M; Heckenlively, J R; Trabulsi, E; Klingaman, R; Bech-Hansen, N T; LaRoche, G R; Pagon, R A; Murphey, W H; Weleber, R G (1993). "Genetic heterogeneity among blue-cone monochromats". Am. J. Hum. Genet. 53 (5): 987–1000. PMC 1682301. PMID 8213841.
  3. Gardner, J C; Webb, T R; Kanuga, N; Robson, A G; Holder, G E; Stockman, A; Ripamonti, C; Ebenezer, N D; Ogun, O; Devery, S; Wright, G A; Maher, E R; Cheetham, M E; Moore, A T; Michaelides, M; Hardcastle, A J (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. PMC 2896775. PMID 20579627.
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