Julie Rosenthal

BASICS

DESCRIPTION

• A progressive degeneration that results in the triad of central vision loss, photophobia, and dyschromatopsia (color vision problems) due to the selective degeneration of cones.

• Cone dystrophy is a heterogeneous disorder both in clinical features and in underlying molecular genetics. The spectrum of cone disorders can be categorized as: (1)

– “Cone Dysfunction Syndromes” that present shortly after birth or during infancy and are stationary (non-progressive). Achromatopsia occurs in 1:30,000, and these infants present with photophobia, poor vision, and pendular nystagmus.

– Cone dystrophies can present anytime during childhood to early adulthood and are progressive.

“Cone-Rod Dystrophies” involve both the rods and cones at an early age, which results in both central vision problems as well as poor night vision.

“Cone Dystrophy” refers to conditions in which the cones are primarily affected. (Of note, many of these patients also have rod dysfunction, but this is less prominent.)

EPIDEMIOLOGY

Prevalence

1/40,000

RISK FACTORS

Family history of cone dystrophy.

Genetics

Most cases of cone dystrophy are sporadic, but autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns have been reported. Autosomal dominant is the most common inherited form.

PATHOPHYSIOLOGY

• Cone degeneration is thought to be the primary event. Subjective visual loss, and decreased visual acuity occur before any ophthalmoscopic changes can be seen.

• There are 3 major subtypes of cones, all of which are affected, therefore color defects will be present along all color axes, sometimes progressing to complete color vision loss over time.

• Varying degrees of rod degeneration can occur over time in some patients.

ETIOLOGY

Several affected genes and their chromosomal loci have been identified, including COD2 (Xq27), RCD1 (6a25-q26), RCD2 (17p12-p13), GUCA1 A, RPGR, CNGA3, and CNGB3 (1).

COMMONLY ASSOCIATED CONDITIONS

• There are several inherited systemic conditions that have cone-rod dystrophy as a component:

– Neurofibromatosis I

– Amelogenesis

– Spinocerebellar Ataxia type 7

– Pierre-Marie Ataxia

– Trichomegaly

– Bardet-Biedl Syndrome

– Alstrom Syndrome

DIAGNOSIS

HISTORY

• Cone dystrophy causes photophobia, loss of visual acuity, and color vision abnormalities

• Symptoms typically occur before age 20 years

• Color vision problems are usually noted early in the course of the disease, in contrast to other macular dystrophies

• Earlier onset of symptoms is associated with more severe disease

• Nyctalopia in the setting of photophobia and visual acuity/color vision loss points more toward a Cone-Rod Dystrophy

PHYSICAL EXAM

• Funduscopic examination

– May be normal in many cases as cone dysfunction occurs before any ophthalmoscopic changes can be seen

– Quite variable, ranging from subtle macular granularity to a well-demarcated, circular, depigmented area of macular atrophy (bull’s-eye maculopathy)

– Optic discs may have temporal pallor

• Visual acuity can range from 20/20 to counting fingers

• Color vision testing with the Hardy-Rand-Rittler plates and/or the Farnsworth-Munsell 100-Hue test will reveal varying degrees of abnormality

DIAGNOSTIC TESTS & INTERPRETATION

Imaging

Initial approach

• Electroretinogram (ERG)

– One of the most important diagnostic tests, as deficits on the ERG occur before changes on ophthalmoscopy are noted

– Patients should undergo full-field and multifocal ERG

– The characteristic finding is markedly abnormal photopic (cone) responses with normal to slightly abnormal scotopic (rod) responses

– Selective diminution of the photopic ‘B’ wave along with decreased amplitude of the 30 Hz flicker may be seen

• Optical Coherence Tomography (OCT) may show transverse photoreceptor loss with disruption/focal loss of the inner segment-outer segment junction

• Fundus autofluorescence shows foveolar hyper-autofluorescence as a nonspecific manifestation in some patients (2)

• Fluorescein angiography can demonstrate early hyperfluorescence

• Visual field testing may show full peripheral fileds, but often have bilateral central scotomas

Follow-up & special considerations

Of note, a study of a large family with AD cone dystrophy found that no single test or finding was adequate to make the diagnosis. Thus, a constellation of history, physical examination, and diagnostic tests should be used, especially in more mildly affected individuals (3).

Pathological Findings

• There are few studies in the literature.

– One study of a 69-year-old male with X-linked cone-rod dystrophy due to a mutation in RPGR showed focally absent RPE in the macula with the remaining RPE showing abnormal pigmentation (hypo- or hyper-). Cones and rods were absent in the perifovea, whereas the remaining retina showed some cone loss but near-normal rod numbers. All photoreceptors had shortened outer segments (4).

DIFFERENTIAL DIAGNOSIS

• Includes Stargardt’s Disease, hereditary optic atrophies, and toxic maculopathy

• Must differentiate from cone-rod dystrophies, which present with similar symptoms, but also has severe rod dysfunction (nyctalopia)

TREATMENT

ADDITIONAL TREATMENT

General Measures

Red contact lenses have been shown to alleviate. In one study, 23 out of 23 subjects showed immediate resolution of light aversion and experienced dramatic improvement in visual function (5).

Issues for Referral

• Patients may benefit from referral to a low vision specialist.

• As vision declines, patients may have to cope with multiple social difficulties, which may include loss of employment, loss of independence, depression, and so on. Patients may benefit from referral to appropriate professionals to enable them to better cope with these issues.

Additional Therapies

• Stem cell therapy

– Parameswaran et al. (6) recently successfully programmed differentiated mouse fibroblast cells to a pluripotent state from which they were successfully reprogrammed using different developmental cues into cones, ganglion cells, and rods.

• Photoreceptor transplantation

– Replacement of defective photoreceptor cells through transplantation of developing photoreceptors has restored vision in blind mice (7).

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Patients should be followed periodically to monitor changes in vision, color vision, and rod function (ERG).

• Refer for low vision services as indicated.

PATIENT EDUCATION

Genetic counseling on the suspected mode of inheritance, if any, can be helpful to patients in providing knowledge of the likelihood that other family members may be affected

PROGNOSIS

• Variable. Some patients will experience severe vision loss.

• Earlier onset of symptoms portends a more severe manifestation of the disease.

• The later the onset of symptoms, the better the prognosis.

COMPLICATIONS

Blindness, loss of color vision.

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