Achromatopsia is a rare cause of infantile nystagmus primarily characterized by reduced or complete loss of color discrimination, reduced visual acuity, and photophobia. Estimated prevalence is 1 in 30,000 individuals. The nystagmus is usually horizontal, symmetric, high frequency, and small amplitude. Hyperopia may be present. Visual acuity is variable, ranging from 20/70 to legal blindness. The disorder is often divided into complete and incomplete forms, the latter being less severe. The fundus is usually normal, but macular changes and vessel narrowing may be present in some individuals. Patients may also have paradoxical pupillary constriction when transitioned from photopic to scotopic conditions. The disorder is due to incomplete and maldevelopment of cone cells.
26.2 Molecular Genetics
Five genes have been associated with achromatopsia: CNGB3 (8q21.3), CNGA3 (2q11.2), GNAT2 (1p13.1), PDE6C (10q24), and PDE6H (12p13). Their protein products are expressed in cone cells and all are involved in phototransduction, involving the guanosine binding site of the transducin alpha subunit (GNAT2), the alpha subunit of the cone phosphodiesterase (PDE6C), the inhibitory gamma subunit (PDE6H), and the cGMP-gated cation channels (CNGA3/CNGB3). CNGB3 and CNGA3 are associated with up to 50 and 25% of cases, respectively. In CNGB3, the most typical mutation found is c.1148delC (70%). Most patients who present with mutations in CNGA3, CNGB3, GNAT2, and PDE6C have complete achromatopsia as compared to those with PDE6H mutations who usually present with the incomplete form.
Among Israeli and Palestinian patients who reside in Jerusalem, CNGA3 mutations are the leading cause of achromatopsia. Two CNGA3 founder mutations are found in approximately 50% of cases. These pathogenic variants lead to a high achromatopsia prevalence (1:5,000).
26.3 Differential Diagnosis
26.3.1 S (Blue) Cone Monochromacy
This X-linked condition is distinguished from achromatopsia with electrophysiology testing and color vision testing.
26.3.2 Cone Dystrophies
Cone function is normal at birth with a delayed onset of nystagmus as cones degenerate. Symptoms are progressive, including reduced visual acuity, photophobia, and abnormal color vision. Progressive macular pigmentary and atrophic changes may be seen. Color vision is initially normal and then declines.
26.3.3 Alström Syndrome
Although Alström syndrome may present with features indistinguishable from achromatopsia clinically or by electroretinogram (ERG), the disorder is progressive and rod involvement is inevitable with blindness often by the second or third decade of life. Patients may also have obesity, diabetes, hearing loss, and cardiomyopathy.
26.4 Uncommon Manifestations
Progressive retinal degeneration, with an evolving cone dystrophy picture, may occur, especially later in life.
26.5 Clinical Testing
Photopic responses are absent or markedly diminished, while the scotopic response is usually normal.
26.5.2 Color Vision Tests
Patients may learn to recognize patterns and differences in brightness, but individuals with achromatopsia have altered color discrimination in all three axes of color vision testing.
26.5.3 Optical Coherence Tomography
Optical coherence tomography (OCT) is often normal, distinguishing this condition from cone dystrophy. Rarely, patients may exhibit variable degrees of foveal hypoplasia, inner/outer segment junction disruption, or macular retinal pigment epithelium (RPE) attenuation.
26.5.4 Systemic Evaluation
It is important to ensure that patients do not have features of Alström syndrome, in particular because the cardiomyopathy can be life-threatening.
26.6 Genetic Testing
One approach is to first perform CNGB3 sequencing or targeted mutation analysis for the common c.1148delC. CNGA3