Blue Cone Monochromatism: A Case Report with Opsoclonus and Light Exposure

Abstract

Blue cone monochromatism (BCM) is a rare X-linked congenital vision disorder that is characterized by a cone dysfunction. We present a case of a 3-year-old boy referred to our department with abnormal eye movements since birth, impaired vision, and difficulties in distinguishing colors. A tendency to stare at the sun was noted. Examination revealed severe loss of visual acuity, high myopia, and opsoclonus. A mutation screening of OPN1LW / OPN1MW gene cluster was performed showing a nucleotide substitution encoding a Cys203Arg (C203R) missense mutation. The diagnosis of BCM in this case was clear and the patient harbored the most frequent genetic alteration. Opsoclonus and continued voluntary light exposure are novel features that have not been previously reported in BCM.

Introduction

Blue cone monochromatism (BCM, OMIM no.: 303700) is a rare X-linked congenital vision disorder. It is characterized by a cone dysfunction starting at birth, affecting approximately 1 in 100,000 individuals. ¹ BMC typically presents with decreased visual acuity (6/60–6/24), nystagmus, photophobia, and myopia. ²

Normal human color vision depends on excitation of three different cone photoreceptors: long wavelength sensitive (L), medium wavelength sensitive (M), and short wavelength sensitive (S) cones, which are maximally sensitive to wavelengths of light perception for red, green, and blue colors, respectively. In BMC, a dysfunction of L and M cones is inherited. Therefore, visual function is limited to S cones and rod photoreceptors activity from birth. ²

Regarding the genetic cause of this disease, the genes that encode L and M cone opsins are OPN1LW and OPN1MW . They are located on a gene cluster on chromosome Xq28, arranged in a head-to-tail tandem where a single OPN1LW is followed by one or more OPN1MW copies. The expression of these genes is regulated by the locus control region (LCR), located upstream of the OPN1LW / OPN1MW gene cluster. Genetic mutations causing BCM have been described in both the OPN1LW and the OPN1MW sequences, as well as in the LCR. ³

We present a case of BCM with some novel features, highlighting the importance of a detailed ophthalmic examination in premature infants with visual symptoms. Also, this case underscores the importance of correctly diagnosing the cause of a color vision anomaly, especially to provide parents with accurate prognosis and genetic counseling.

Case Report

A 3-year-old boy was referred to our department because his parents had noticed abnormal eye movements since he was 2 months old. Parents also expressed that their son needed to get close to objects to see them, and showed difficulties in distinguishing colors. Additionally, they were concerned that he stared at the sun when they went outside and he avoided wearing sunglasses.

On examination, his visual acuity measured by preferential-looking tests at 1 m was 2.4 cyc/cm in his right eye (OD) and 3.2 cyc/cm in his left eye (OS). His visual acuity with the Lea symbol chart was 6/60 in both eyes (OU). His spherical equivalence was −8.00 D in his OD, and −7.50 D in his OS. The patient presented sudden chaotic and multidirectional conjugated ocular movements consistent with opsoclonus. The intensity of this dyskinesia did not decrease in any position. He did not have torticollis. Anterior segment, intraocular pressure, and pupillary reflexes were normal. His fundus examination revealed a tessellated appearance of the retinal periphery. Macular optic coherence tomography revealed no signs of solar retinopathy.

Family history was significant for a cousin recently diagnosed with BCM. He was highly myopic and presented with no obvious photophobia and difficulty in distinguishing colors.

Based on family history, a mutation screening of OPN1LW / OPN1MW gene cluster was performed. Sequence analysis of OPN1LW exon 4 revealed a c.607T > C nucleotide substitution, encoding a Cys203Arg (C203R) missense mutation. Electroretinogram (ERG) could not be correctly performed as patient was not able to cooperate

After a diagnosis of BMC was reached, optical correction was prescribed and myopia treatment with atropine was discussed. However, due to the genetic origin of the myopia and the lack of data on these patients, a decision was made against this treatment.

Discussion

Cone dystrophies comprise a heterogeneous group of disorders characterized by visual loss, color vision abnormalities, central scotomata, and a variable degree of nystagmus and photophobia. The X-linked cone opsin disorders, which include BCM, display wide inter- and intrafamilial variability, and most of them are stationary. ⁴

In BCM, the most common mutation in the OPN1LW / OPN1MW gene array is caused by nonhomologous recombination followed by a single nucleotide sequence alteration that inactivates the gene. There are three inactivating opsin mutations described, C203R being the most frequently reported. Other mutations observed in BCM include a deletion in LCR sequence and a deletion of an entire exon in L opsin array gene (exon 4). ⁵ The C203 substitution results in the loss of an important disulfide bond necessary for the correct folding of the opsin protein within the tertiary structure. ⁶ Among the three types of cones population, the S cones present the lowest density of cones photoreceptor (representing 2–7% of cones). A significant reduction in cone density, disruption in the cone mosaic, and thinning of the outer nuclear layer of the retina have been observed in patients harboring the C203R mutation. ⁷

Other color vision disorders that may present with similar clinical features should be considered in the differential diagnosis. In rod monochromatism, there is an absence of functioning cone photoreceptors and visual perception depends almost exclusively on rods. It is inherited in an autosomal recessive pattern. In comparison to rod monochromatism, patients with BCM display better color judgments in the Farnsworth 100 Hue test, and they may also display protan-like ordering patterns on the Farnsworth D-15. ⁸ BCM can also be distinguished from rod monochromatism in the ERG outcomes. Single-flash photopic ERG is reduced in both, but the S-cone ERG is well preserved in BCM. ^{4 8} Bornholm disease, another X-linked cone dystrophy, shares clinical manifestations with BCM, but patients with this disorder have additional findings including high astigmatism, moderate optic nerve head hypoplasia, thinning of the retinal pigment epithelium, and abnormal photopic ERG. ^{4 9}

BCM remains without a cure, yet gene therapy research studies on a mouse model g are demonstrating regeneration of outer cone segments after subretinal injection of adeno-associated virus type-5 vectors. ¹⁰

This patient's clinical manifestations were typical for BCM, except for opsoclonus and the continued voluntary light exposure. The patient presented with opsoclonus, that is, sudden chaotic and multidirectional conjugated ocular movements that persisted during sleep, instead of the expected rhythmic regular ocular movements (nystagmus). Opsoclonus usually reveals deeper impairment than nystagmus, hence the presence of opsoclonus in this case could reveal a more severe form of BCM.

Upon ophthalmological examination, no signs of solar retinopathy were observed, neither actinic keratitis was found. Hence, the continued voluntary light exposure clinically diagnosed, probably implies that the child was not obviously photophobic, instead of presenting clear photophilia. We have not established an explanation that answers why the patient had the tendency to stare at sun, contrary to other BCM, which commonly present photophobia. However, the fact that the cousin has no obvious photophobia, supports the association of this symptom with the genetic causes of BCM. To the best of our knowledge, this is the first case of BCM with opsoclonus and tendency to light exposure.

Conclusion

In conclusion, BCM is a rare X-linked congenital vision disorder that typically presents with decreased visual acuity, nystagmus, photophobia, and myopia starting at birth. Albeit the diagnosis of BCM in this case was clear and the patient harbors the most frequent genetic alteration, opsoclonus and continued voluntary light exposure have not been previously reported in this disorder. This highlights the importance of thorough investigation of visual disturbances in childhood and the need for genetic confirmation in many cases given the different clinical presentations.