Cone dystrophy is a group of inherited retinal diseases characterized by progressive impairment of cone photoreceptor function. Cones are responsible for color vision and central visual acuity; their dysfunction leads to early onset of decreased visual acuity, photophobia, and color vision abnormalities.
The overall prevalence of inherited retinal dystrophies (IRD) is approximately 1/2,000 to 1/3,000, and cone dystrophy constitutes a part of them. 1) The prevalence of cone dystrophy alone is estimated at about 1/30,000 to 1/40,000. 4)
When rod function also declines with progression, it is called cone-rod dystrophy. In practice, many cases show reduced rod responses in advanced stages, and most eventually progress to cone-rod dystrophy. 4)
Comparison with retinitis pigmentosa (RP): RP is a rod-cone dystrophy where rod photoreceptors are affected first, with night blindness as an early symptom. In cone dystrophy, cones are affected first, so day blindness, photophobia, color vision abnormalities, and decreased visual acuity are early symptoms, and night blindness does not appear initially.
Cone dystrophy is a selective impairment of cone function, with rod function preserved in the early stages. Therefore, there is no night blindness initially, and visual function in dark conditions is relatively good. However, as the disease progresses and rods become affected, it transitions to cone-rod dystrophy, with night blindness and visual field constriction also appearing. Few cases remain as pure cone dystrophy clinically, and most eventually progress to cone-rod dystrophy. 4)
| Disease stage | Main symptoms | Rod function | Key points for differentiation |
|---|---|---|---|
| Early stage | Decreased vision, photophobia, color vision abnormality | Normal | In contrast to retinitis pigmentosa (RP presents with night blindness initially) |
| Advanced stage | Above plus night blindness, visual field constriction | Decreased | Transition to cone-rod dystrophy |
Fundus findings:
ERG findings (essential for definitive diagnosis):
In early stages or some types, the fundus may appear normal. Therefore, it can be missed by fundus examination alone, and ERG is essential for diagnosis in patients complaining of decreased vision, photophobia, and color vision abnormalities. Bull’s eye maculopathy is a typical finding, but it may only be clearly visualized by fluorescein angiography.
Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked. In genetic counseling, determining the inheritance pattern is important for assessing familial risk.2)
Phototransduction Cascade-Related Genes
GUCA1A (6p21.1): Encodes guanylate cyclase activating protein 1 (GCAP1). Mostly autosomal dominant. Involved in cGMP regulation.5)
GUCA1B (6p21.1): Encodes GCAP2. Similar function to GUCA1A. Autosomal dominant.
GUCY2D (17p13.1): Encodes retinal guanylate cyclase (RetGC-1). Autosomal dominant. Involved in cGMP synthesis. Also a causative gene for Leber congenital amaurosis.5)
Structural/Transcription-Related Genes
RDS/PRPH2 (6p21.1): Encodes peripherin 2. Involved in disc membrane structure of photoreceptor outer segments. Causes destabilization and degeneration of outer segments.4)
CRX (19q13.33): A transcription factor necessary for cone and rod differentiation and maintenance. Autosomal dominant. Abnormal expression patterns lead to photoreceptor degeneration.4)
Retinal metabolism-related genes
ABCA4 (1p22.1): ATP-binding cassette transporter. Involved in the removal of all-trans-retinal from the outer segment. Autosomal recessive inheritance. 5)
Mutations lead to lipofuscin accumulation → RPE and photoreceptor toxicity → cone degeneration. It is also a major causative gene for Stargardt disease, and depending on the type of mutation, it forms a spectrum of Stargardt disease, cone dystrophy, and cone-rod dystrophy. 6)
It is a hereditary disease and can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns. In autosomal dominant inheritance, vertical transmission from parent to child occurs, with a 50% risk for each child. In autosomal recessive inheritance, if both parents are carriers, the risk for a child is 25%. Many causative genes have been reported, and genetic testing may identify them. Since the risk within a family differs by inheritance pattern, consultation with a genetic specialist or certified genetic counselor is recommended. 2)
ERG is essential for definitive diagnosis, and genetic testing to identify the causative gene is recommended. 2)
ERG (electroretinogram)
Gold standard for diagnosis: Even in types with normal fundus findings, diagnosis is possible with ERG
Characteristic findings of cone dystrophy:
Advanced stage findings: Rod response also decreases → indicates progression to cone-rod dystrophy
Imaging tests
Fluorescein angiography (FA): Useful for confirming bull’s eye maculopathy. The target macular pattern is more clearly delineated than with ophthalmoscopy
OCT: Evaluation of foveal outer layer structure. Allows quantitative assessment of changes or loss of the ellipsoid zone (EZ). 4)
Fundus autofluorescence (FAF): Detection of abnormal fluorescence patterns in the macula. Useful for assessing disease activity. 4)
Genetic testing and others
Genetic testing: IRD genetic panel testing (next-generation sequencing) is recommended, following the IRD genetic testing guidelines 2)
Color vision testing: Assess the degree and axis of color vision deficiency using Ishihara color plates, Panel D-15, and anomaloscope
Visual field testing: Detection of central scotoma. Goldmann perimeter or static automated perimeter
Significance of genetic identification: Confirms diagnosis, enables genetic counseling, and determines eligibility for gene therapy clinical trials 2)
| Disease name | Age of onset | Main symptoms | ERG findings | Key differentiating points |
|---|---|---|---|---|
| Retinitis pigmentosa (rod-cone dystrophy) | Childhood to adolescence | Night blindness → visual field constriction → decreased visual acuity | Early rod response reduction | Rod function impaired first. Night blindness is the initial symptom. |
| Stargardt disease | 10s to 20s | Decreased visual acuity, central scotoma | Normal to mildly abnormal | ABCA4 mutation. Yellowish flecks in macula. ERG relatively preserved. |
| Congenital color vision deficiency | Congenital | Color vision only | Normal | Non-progressive. Normal visual acuity and ERG. Only color vision abnormality. |
| Achromatopsia | Congenital | Decreased vision, nystagmus, photophobia, loss of color vision | Cone loss, rod normal | Congenital, non-progressive. CNGA3/CNGB3 mutations. 3) |
| Hydroxychloroquine retinopathy | After drug use | Decreased vision, color vision abnormality | Cone attenuation | Differentiated by history of drug use. Similar to bull’s eye finding. |
ERG (electroretinogram) is essential for definitive diagnosis. Marked reduction or absence of cone responses (30-Hz flicker) with preserved rod responses is characteristic. Since some types have a normal-appearing fundus, performing ERG is key to diagnosis in patients with decreased vision, photophobia, and color vision abnormalities. Genetic testing is recommended for definitive diagnosis, and identification of the causative gene is important for genetic counseling and future treatment options. 2)
There is no established effective treatment, and symptomatic and supportive care are the mainstays.
| Treatment | Purpose | Details |
|---|---|---|
| Light-filtering lenses | Reduction of photophobia | Select appropriate gray or brown filters for each patient. Effective for improving QOL. |
| Refractive correction | Maximizing visual acuity | Prescribe appropriate glasses or contact lenses. |
| Low vision care | Daily living support | Magnifiers, magnifying reading devices, digital magnifiers, smartphone apps, text-to-speech. |
| Social support | Ensuring quality of life | Utilization of disability certificates and assistive device subsidy programs. |
Identification of the causative gene through genetic testing is necessary to confirm the inheritance pattern and assess familial risk. Genetic testing is recommended in preparation for future participation in gene therapy clinical trials. 2)
Currently, there is no established treatment to restore vision. Management focuses on reducing photophobia with light-filtering lenses and low vision aids such as magnifiers and magnifying reading devices. Gene therapy research is ongoing, with preclinical studies targeting major causative genes for cone dystrophy (e.g., GUCY2D, GUCA1A). Genetic testing is recommended in preparation for future treatment development. 2)
The normal phototransduction mechanism in cone photoreceptors is as follows:
Gene therapy for inherited retinal dystrophies (IRD) as a whole is advancing rapidly. Following the approval of voretigene neparvovec (Luxturna) for RPE65-associated IRD, development of therapies targeting other genes is progressing. 1) Since the efficacy of gene therapy depends on the number of remaining photoreceptor cells, intervention in childhood or early stages of the disease is considered important. 1)
