Achromatopsia

DEFINITION/OVERVIEW

Achromatopsia, also known as rod monochromatism, is a nonprogressive congenital dysfunction of cone photoreceptors leading to decreased central vision. It is a relatively rare condition, with an incidence of 1 in 30,000. There are three main types of achromatopsia categorized by the extent of cone photoreceptor dysfunction: complete, incomplete, and bluecone monochromatism. Due to their relative or complete absence of cone (color) receptors, patients tend to function better under dimly lit conditions (scotopic) rather than brightly lit conditions (photopic). Because the fovea has a relatively high density of cone photoreceptors, central visual acuity is affected in this condition. The degree of visual impairment varies from mild to severe in accordance with percentage of affected cones and type of achromatopsia.

ETIOLOGY

Both complete and incomplete types of achromatopsia are AR-inherited, although incomplete achromatopsia may also be inherited in an X-linked manner. Several genes, including CNGA3 (Chr 14), CNGB3 (Chr 14), and GNAT2 (Chr 1p13), have been linked to 60% of the cases of achromatopsia.8 Blue-cone monochromatism is also inherited via the long arm of the X chromosome, specifically on Xq28.

Histologic studies have shown that patients with achromatopsia have substantially fewer cones in both the extrafoveal and foveal areas. This reduction may be on the order of 95–100% in patients with complete achromatopsia. The morphology of the remaining cones has also been shown to be abnormal, with increased number of ectopic nuclei.5 Blue-cone monochromatism affects only blue cones; red-green cones continue to function normally.

CLINICAL PRESENTATION

Children with poor central vision may present with a sensory, roving nystagmus and poor visual attention and tracking. Visual acuity in infancy and childhood ranges from 20/120–20/200. The oculodigital reflex is an ominous sign of poor vision. Progression of vision loss is rarely seen. Other important clinical findings include observation of a paradoxical pupillary response (direct, bright

light stimulus causes dilation as opposed to the expected constriction of the pupil), which is characteristic of achromatopsia and CSNB. Refractive errors including moderate (greater than 3 diopters) hyperopia and astigmatism may also be observed.

By definition, patients with achromatopsia have no structural anomalies on ophthalmologic exam and have no known neurologic diseases (173, 174). The definitive diagnosis is by ERG, which shows an absent or varying degree of low cone-mediated response compared with age-matched normal patients. The rod-mediated responses on ERG are normal. In contrast to LCA, no systemic disorders have been associated with achromatopsia.

DIFFERENTIAL DIAGNOSIS

The diagnosis of achromatopsia cannot be differentiated from LCA or CSNB on initial clinical examination of an infant. An ERG is needed to determine if the cones are affected relatively more than the rods (achromatopsia affects cones > rods, CSNB affects rods > cones), or if both types of photoreceptors are affected (LCA severely affects both rods and cones).

DIAGNOSIS

Achromatopsia is diagnosed by first excluding all ocular causes of poor vision. Poor vision caused by damage to intracerebral visual pathways including the optic tracts, optic radiations, and occipital lobe, should be evaluated by neurologic examination and MRI. When ophthalmologic, neurologic and radiographic examinations are negative, an ERG is indicated to determine relative functionality of the photoreceptors and the bipolar retinal cells. ERG typically shows nonrecordable function or severely attenuated responses of cone photoreceptors.8

No retinal pigmentary changes are seen in patients with achromatopsia.

MANAGEMENT/TREATMENT AND PROGNOSIS

There are no known treatments that improve the vision in patients with achromatopsia. An important intervention that can be very helpful for patients with achromatopsia and their families is low-vision therapy and social service referrals for infants and children with limited vision.

Achromotopsia is a stable condition. Continued loss of vision is uncommon.

Stargardt disease

DEFINITION/OVERVIEW

Stargardt disease, also known as Stargardt dystrophy or fundus flavimaculatus, is the most common type of juvenile-onset macular dystrophy. However, it is still a relatively rare condition, with an incidence of 1 in 30,000–50,0000 (7% of all retinal dystrophies). As the name implies, patients with Stargardt macular dystrophy demonstrate a degenerative change within the macula which ultimately affects central visual acuity. Symptoms of decreased vision do not generally occur until the second decade of life, but findings of retinal changes may be seen within the first decade of life. This type of macular dystrophy occurs significantly earlier than the adult-onset type known as age-related macular dystrophy, which generally becomes symptomatic in the 6–7th decades of life.

ETIOLOGY

This condition is inherited in an AR manner, due to a dysfunctional protein encoded by the gene ABCA4.9,10 Stargardt disease classically demonstrates an accumulation of a retinal waste product known as lipofuscin within the subretinal space. This occurs as a result of a dysfunctional energy transport protein coded by the gene ABCA4. Lipofuscin is thought to be the waste product or perhaps an accumulation of degenerating photoreceptors, that accumulates because energy transport into the retina is not occurring normally. The deposits block the normal choroidal flush which is usually seen in the early phases of a fluorescein angiogram.

Recent genetic studies have shown that a mutation in the same gene (ABCA4) results in a varied phenotype, ranging from findings historically described as Stargardt disease to findings which had been traditionally called fundus flavimaculatus. It is now believed that these diseases are different phenotypic expressions of the same genotype. Not all of the mutation sites and alleles for the ABCA gene have been identified, and some studies have suggested that current testing for alleles may fail to diagnose or predict which patients will develop Stargardt disease.11

CLINICAL PRESENTATION

Children may fail a vision screening test, but the diagnosis is often not made until after vision has declined enough to affect daily visual function. The visual acuity of patients with Stargardt disease varies with the degree of involvement and the age of diagnosis. Acuities may be normal in early stages, and range from 20/100–20/400 by the 4th decade of life. A characteristic early symptom of visual dysfunction is a complaint of requiring more time to adjust to darkly lit environments after exposure to bright lights (prolonged dark adaptation).

On ophthalmoscopy, a ‘beaten-bronze’ appearance of the retina is classically described and seen in about 85% of cases (175, 176). Fluorescein angiography shows a ‘silent choroid’, as lipofuscin accumulation beneath the level of the retina blocks fluorescence from the choroidal circulation. Some patients show a decreased photoreceptor responses of both rods and cones on ERG testing, but this test is not always abnormal in Stargardt disease.

DIFFERENTIAL DIAGNOSIS

The diagnosis of Stargardt disease or fundus flavimaculatus is differentiated from other macular dystrophies by its classic appearance on direct retinal examination and fluorescein angiogram.

DIAGNOSIS

The diagnosis of Stargardt disease is made by clinical examination, by evaluation of visual acuity, indirect ophthalmoscopy, and fluorescein angiography. ERG, dark adaptation testing, and genetic evaluation are not necessary for the definitive diagnosis, but may be helpful in certain clinical situations.

MANAGEMENT/TREATMENT AND PROGNOSIS

There are no known treatments that improve the vision in patients with Stargardt disease. An important intervention that can be very helpful for patients with Stargardt disease and their families is low-vision therapy and social services referrals for the blind if vision falls below 20/200.

The progression of vision loss is variable and can start with a visual acuity of 20/40 and decrease rapidly (especially in children) to 20/200. By age 50, approximately half of affected people have vision of 20/200–20/400.