# 303700
BLUE CONE MONOCHROMACY; BCM
Alternative titles; symbols
BLUE CONE MONOCHROMATISM
COLORBLINDNESS, BLUE-MONO-CONE-MONOCHROMATIC TYPE; CBBM
Other entities represented in this entry:
SNOMEDCT: 24704003; ORPHA: 16, 1872; DO: 0050679;
Phenotype-Gene Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Blue cone monochromacy | 303700 | X-linked recessive | 3 | OPN1LW | 300822 |
| Xq28 | Blue cone monochromacy | 303700 | X-linked recessive | 3 | OPN1MW | 300821 |
TEXT
A number sign (#) is used with this entry because of evidence that blue cone monochromacy can be caused by alteration in the red (OPN1LW; 300822) and green (OPN1MW; 300821) visual pigment gene cluster on chromosome Xq28 or in the locus control region for the red and green pigment genes (300824), located adjacent to and 5-prime of the pigment gene cluster.
Description
Blue cone (OPN1SW; 613522) monochromatism is a rare X-linked congenital stationary cone dysfunction syndrome characterized by the absence of functional long wavelength-sensitive and medium wavelength-sensitive cones in the retina. Color discrimination is severely impaired from birth, and vision is derived from the remaining preserved blue (S) cones and rod photoreceptors. BCM typically presents with reduced visual acuity, pendular nystagmus, and photophobia. Patients often have myopia (review by Gardner et al., 2009). There is evidence for progression of disease in some BCM families (Nathans et al., 1989; Ayyagari et al., 2000; Michaelides et al., 2005).
Nomenclature
Blue cone monochromatism was formerly called 'incomplete achromatopsia' or 'atypical achromatopsia.'
Clinical Features
The first detailed description of blue cone monochromacy is that given by Huddart (1777). The subject of that report '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.' This disorder was previously interpreted as total colorblindness. Information presented by Spivey (1965) indicated that affected persons can see small blue objects on a large yellow field and vice versa.
See comments of Alpern et al. (1960). Blackwell and Blackwell (1961) described affected families in which a few blue cones seemed to be present.
Reitner et al. (1991) performed wavelength discrimination experiments in 5 male patients with blue cone monochromacy and found that within the limited intensity range at which rods and blue cones are simultaneously active, color vision is possible. The authors noted that these findings imply that some rod and cone signals travel by separate pathways to the visual processing stage where wavelength discrimination takes place.
Andreasson and Tornqvist (1991) reported 3 Swedish families with a diagnosis of X-linked achromatopsia, in which affected individuals showed blue cone monochromacy on color vision testing. In 1 family, all 7 patients displayed characteristic BCM, with myopia, low visual acuity, and typical color test results; only 2 of the 7 affected individuals had a measurable b-wave response to 30-Hz flickering light. In contrast, the other 2 families showed better visual acuity, myopia was not obligate, and with the use of a narrow bandpass filter, residual cone b-wave responses were measurable in all 4 patients. Andreasson and Tornqvist (1991) suggested that there might be different types of X-linked achromatopsia, including some with a more benign prognosis.
Michaelides et al. (2005) described 3 British families with X-linked recessive BCM, 2 of which showed evidence of progression of disease: the 60-year-old and 70-year-old maternal grandfathers from families 'A' and 'C,' respectively, tested as an achromat and a rod monochromat, respectively, and both showed mild macular retinal pigment epithelial (RPE) changes, whereas their respective affected grandsons displayed residual color discrimination and had normal-appearing fundi.
Cone Dystrophy 5
Gardner et al. (2010) examined 4 affected males and 2 carrier females from a 3-generation British family that was ascertained as having an X-linked progressive cone dystrophy, with blue cone monochromacy on color vision testing. Affected individuals were between 14 and 82 years of age and reported onset of reduced central vision in the first decade, with subsequent gradual deterioration of visual acuity and color vision. One patient had nystagmus; the others reported no history of nystagmus. The appearance of the macula ranged from mild retinal pigment epithelial changes in younger individuals to extensive macular atrophy in the older generation. Autofluorescence imaging was normal in the 3 youngest affected individuals, but the 82-year-old male patient showed bilateral perimacular rings of increased autofluorescence. Electroretinograms (ERGs) in all 4 affected individuals were consistent with severe generalized cone system dysfunction with preserved or relatively preserved rod function; all 4 had undetectable pattern ERGs, consistent with severe macular dysfunction. Color vision testing in the 3 youngest patients revealed good tritan discrimination with no measurable discrimination along protan or deutan axes. No discernible color discrimination was possible in the 82-year-old patient because of poor visual acuity; however, psychophysical experiments established that he had only minimal residual S-cone function at the macula. Noting the progressive nature of disease in this family, as well as the evidence of macular RPE disturbance even in younger patients, Gardner et al. (2010) stated that the phenotype was more consistent with progressive cone dystrophy than with BCM.
Inheritance
Bromley (1974) reported a large kindred with this disorder in a typical X-linked recessive pattern.
Population Genetics
Blue cone monochromatism affects approximately 1 in 100,000 individuals (review by Gardner et al., 2009).
Mapping
Lewis et al. (1987, 1987) showed linkage of blue cone monochromatism to 2 DNA markers (DXS15 and DXS52) that map in the Xq28 area. Southern blot analysis with clones derived from the red (300822) and green (300821) cone pigment genes showed loss or rearrangement of the cone pigment cluster, but in none of the 3 multigenerational families studied were all pigment genes missing.
In a 3-generation British family with X-linked progressive cone dystrophy, in which mutation in the RPGR gene (312610) had been excluded, Gardner et al. (2010) performed X-chromosome haplotype analysis and demonstrated that markers on Xp did not segregate with disease, thus excluding the RP2 (300757) and CACNA1F (300110) genes. A common haplotype that segregated with disease was found on Xq, and recombination events defined a 26-Mb interval on Xq26.1-qter between markers DXS1047 and DXS984. Calculation of 2-point lod scores for markers on Xq yielded a significant lod score of 2.41 at DXS8045 (theta = 0) on Xq27.3.
Molecular Genetics
In all 12 families with blue cone monochromacy (BCM) studied by Nathans et al. (1989), alterations were observed in the red and green visual pigment gene array. The alterations fell into 2 classes: one class, seen in 4 families, arose by a 2-step pathway consisting of unequal homologous recombination and point mutation; the second class, present in 12 families, arose by nonhomologous deletion of genomic DNA adjacent to the red and green pigment gene cluster. These deletions defined a 579-bp critical interval (locus control region (LCR); 300824) located 4 kb upstream of the red pigment gene and 43 kb upstream of the nearest green pigment gene. Individuals with the 2-step alteration presumably started out as dichromats in whom homologous unequal recombination had reduced to 1 the number of genes in the tandem array of cone pigment genes, as is seen in approximately 1% of Caucasian X chromosomes; 3 of the 4 2-step families had a single 5-prime red, 3-prime green hybrid gene, and 1 family had a single red gene. In the second step, a mutation inactivated the remaining gene; Nathans et al. (1989) identified 4 nucleotide changes, including a C203R substitution in the red-green hybrid gene present in 3 families (see, e.g., 300821.0002). Regarding the second class of alteration, the authors made an analogy to 2 forms of thalassemia (see 141900) in which absence of distant upstream sequences results in loss (in cis) of beta-globin gene expression, supporting a model in which distant sequences act to coordinate tissue-specific gene expression. In addition, Nathans et al. (1989) noted that although most persons with blue cone monochromacy have retinas that appear normal, in some patients a progressive central retinal dystrophy is observed as they grow older. The dystrophic region corresponds to the fovea, the cone-rich area responsible for high acuity vision, and the immediately surrounding retina. Nathans et al. (1989) suggested that, by analogy, some peripheral retinal dystrophies may be caused by mutations in the genes encoding rhodopsin (RHO; 180380) or other rod proteins.
Nathans et al. (1993) examined the tandem array of red and green cone pigment genes on the X chromosome in 33 unrelated male patients with BCM or closely related variants of BCM. In 24 subjects, 8 genotypes were found that would be predicted to eliminate the function of all of the genes within the array. As observed in an earlier study (Nathans et al., 1989), the rearrangements involved either deletion of the LCR adjacent to the gene array or loss of function via homologous recombination and point mutation. All of the deletions encompassed the common LCR region between 3.1 kb and 3.7 kb 5-prime of the array. In 15 probands who carried a single gene, an inactivating C203R mutation was found, and both visual pigment genes carried the mutation in 1 subject whose array had 2 genes (see 300822.0003 and 300821.0002). This mutation was also found in at least one of the visual pigment genes in 1 subject whose array had multiple genes and in 2 of 321 control subjects, suggesting that preexisting C203R mutations constitute a reservoir of chromosomes that are predisposed to generate blue cone monochromat genotypes by unequal homologous recombination and/or gene conversion. Two other point mutations were identified: arg247 to ter (R247X; 300822.0001) in an individual (patient 'MP') previously studied by Reitner et al. (1991) with a single red-pigment gene, and pro307 to leu (P307L) in an individual with a single 5-prime-red/3-prime-green hybrid gene. The observed heterogeneity of genotypes pointed to the existence of multiple 1- and 2-step mutation pathways to blue cone monochromacy.
In a Danish family with BCM, Ladekjaer-Mikkelsen et al. (1996) identified an isolated red pigment gene with deletion of exon 4 (300822.0005). The authors stated that this was the first intragenic deletion reported among the red and green pigment genes and that it represented a third mechanism underlying the development of BCM.
Ayyagari et al. (2000) studied 10 unrelated families segregating X-linked recessive BCM. Examination of affected individuals revealed progressive macular atrophy in a 56-year-old male patient and his 70-year-old carrier sister. In addition, 4 patients from 3 families had considerable unexplained residual photopic b-wave response on electroretinography (30 to 80% of the clinical low-normal value). Nine of the 10 families had deletions in the upstream red pigment gene region ranging from 6.3 to 17.8 kb; all of the deletions included the 600-bp LCR and part or all of the red gene. The remaining family showed loss of all of the exons of the green pigment gene. Ayyagari et al. (2000) stated that they observed no association between the phenotypes and genotypes in these families.
Michaelides et al. (2005) studied 3 British families with X-linked recessive BCM, 2 of which showed evidence of progression of disease. In 1 of the pedigrees with progressive disease and in the family with typical BCM, the authors identified a single 5-prime-L/M-3-prime hybrid gene that also carried the C203R substitution in exon 4. In the remaining pedigree ('family A'), the mutational basis of the color vision defect was not identified.
Gardner et al. (2009) analyzed 3 British families with BCM, 1 of which was a family with a slowly progressive phenotype previously described by Michaelides et al. (2005) ('family A'). In all 3 families, genetic analysis revealed an unequal crossover within the opsin gene array and an inactivating mutation: in 1 family, affected individuals had a single 5-prime-L/M-3-prime hybrid gene with an inactivating C203R mutation, whereas in another family, 11-year-old adopted twin brothers with BCM had a C203R-inactivated hybrid gene followed by a second inactive gene. The family with documented progressive disease was found to have a single hybrid gene lacking exon 2.
Cone Dystrophy 5
In a 3-generation British family with X-linked progressive cone dystrophy mapping to Xq27.3, Gardner et al. (2010) demonstrated that the cone opsin gene array in affected members consisted of an LW gene containing a W177R (300821.0006) mutant MW exon 3, followed by an MW gene containing an identical W177R mutation in exon 3. Analysis of the intervening sequence flanking the mutant MW exon 3 of both genes indicated that W177R was transferred in a block of exon 3 sequence from the MW gene into the LW gene by gene conversion.
See Also:
Sloan (1954); Wang et al. (1992)REFERENCES
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