NORTH CAROLINA MACULAR DYSTROPHY

North Carolina macular dystrophy is inherited as an autosomal dominant trait. The onset of this condition is usually early in life.

Symptoms

Patients usually present with progressive central visual loss. Symptoms start very early, typically becoming stabilized at the end of the first decade of life.

Clinical Features

The clinical presentation of North Carolina macular dystrophy is highly variable. At the earlier stages of the condition, the visual acuity may be good, with drusen in the macular area. As the disease progresses, the drusen increase in number and become confluent. The condition may show a further progression to an end-stage state characterized by macular staphylomas.

Ancillary Testing

Individuals affected with this condition may show a central scotoma on visual field testing. However, peripheral visual fields, color vision, electroretinogram, and electrooculogram are typically normal.

Fluorescein angiography shows window defects that correspond to the drusen. The staphylomatous lesion in the end stage of the condition is hypofluorescent on fluorescein angiography due to chorioretinal atrophy.

Pathology/Pathogenesis

No histopathologic studies have been reported. The condition has been mapped to the 6q14-q16.2 locus. A recent histopathologic examination of an eye of a patient with North Carolina macular dystrophy showed loss of photoreceptors and retinal pigment epithelium as well as choriocapillaris atrophy localized to the macula.

Treatment/Prognosis

There is no known treatment for North Carolina macular dystrophy. It is a hereditary condition that usually stabilizes by 10 years of age. Visual acuity may range from 20/20 to 20/200.

Systemic Evaluation

There are no known systemic associations of North Carolina macular dystrophy.

North Carolina macular dystrophy is an autosomal dominant disorder, as demonstrated by this series of fundus photographs of a mother and her two sons.

The 34-year-old son of the woman shown in the previous figure had extensive retinal pigment epithelial alterations and chorioretinal atrophy. Pigment clumping may be observed in the macula and peripheral retina.

Fundus photographs of a 57-year-old woman demonstrate macular atrophy. In some cases, the macular lesions have a staphylomatous-like appearance.

The fellow eye of the patient shown in the previous figure revealed prominent retinal pigment epithelial hyperplasia in addition to the chorioretinal atrophy.

The 20-year-old son of the same woman had mild macular changes consisting of central drusen and mild pigmentary changes.

Some of the macular drusen were confluent. No significant retinal pigment epithelial abnormalities were noted.

Retinitis pigmentosa (RP; rod-cone dystrophies) includes a diverse group of inherited retinal dystrophies characterized by a progressive degeneration of the photoreceptor cells. The majority of cases of RP are sporadic and have no clear identifiable family history. However, some hereditary patterns have been described: autosomal dominant (20%); autosomal recessive (15%); and X-linked recessive (10%). The age at onset varies, depending on the inheritance pattern. X-linked cases usually have an earlier onset and autosomal dominant cases tend to have a later onset of the condition.

Symptoms

The typical symptoms of RP include nyctalopia and progressive peripheral visual loss. Central vision is usually spared in the initial stages of the condition. Eventually, the peripheral visual loss increases, leaving a tunnel of central vision.

Clinical Features

The typical fundus appearance of RP consists of peripheral atrophy of the retina, retinal pigment epithelium (RPE), and choriocapillaris, optic disc pallor, arteriolar narrowing, and retinal pigment migration. These pigmentary changes may be manifested as a diffuse granularity, pigment clumping, or bone spicule-like deposits. Other findings may be cystoid macular edema, wrinkling of the internal limiting membrane, vitreous cells or opacities, posterior subcapsular cataracts, and optic nerve drusen.

There are several presentations of RP. Retinitis pigmentosa sine pigmento is a variant of RP (probably an early stage of RP) in which the typical pigment changes are absent or minimal. Retinitis punctata albescens presents the typical findings of RP in addition to many small white dots at the level of RPE.

Ancillary Testing

Fluorescein angiography shows patches of hyperfluorescence resulting from RPE atrophy, choriocapillaris nonfilling defects, and an increase in the retinal circulation time. Patients with cystoid macular edema often show the typical staining pattern on fluorescein angiography, while in others, only minimal staining can be detected. Visual field testing reveals a midperipheral ring scotoma in the earlier stages that progresses into a constricted visual field with a remaining central tunnel of vision in the late stages of the condition. Dark-adaptation studies show an elevated adaptation curve of the rod segments and a delayed cone-rod break. The electroretinogram is

essential in the evaluation of RP patients. It shows reduced and prolonged a- and b-waves and becomes unrecordable with time.

Pathology/Pathogenesis

Histopathologic studies have revealed photoreceptor degeneration, atrophy of the retina and RPE, migration of RPE cells into the retina, thickening and hyalinization of vessel walls and atrophy, and gliosis of the optic nerve.

A wide spectrum of genotypes exist in this condition. Approximately 26 RP genes have been identified and mapped to different loci (chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 14, 15, 16, 17, 19, X). More than 70 mutations in the rhodopsin gene have been identified as responsible for autosomal dominant RP. Defects in

the peripherin gene also have been recognized as the etiology in some cases of autosomal dominant RP. Mutations in the genes coding for ROM1 protein and cGMP phosphodiesterase have also been identified in some RP patients.

Treatment/Prognosis

This condition is characterized by a slowly progressive course. Total blindness is unusual. Patients with RP should be followed up on a yearly basis. If present, cystoid macular edema may be treated with acetazolamide. Cataracts can be extracted if they are visually significant. Therapy for autosomal dominant RP with high doses of vitamin A palmitate (15 000 IU/day) may show a slightly slower rate of progression of the condition. This finding, however, is controversial, as is the reported slightly adverse effect of vitamin E on RP.

Systemic Evaluation

Several systemic diseases are associated with RP or RPlike fundus patterns, such as Usher syndrome (RP and congenital sensorineural hearing loss), Laurence Moon and Bardet-Biedl syndromes, neuronal ceroid lipofuscinosis, Refsum’s disease, abetalipoproteinemia, KearnsSayre syndrome, Alström’s disease, and others.

The classic findings of retinitis pigmentosa include waxy pallor of the optic discs, retinal vessel attenuation, and peripheral pigmentary alterations.

The peripheral pigmentary alterations vary from mild stippling of the retinal pigment epithelium to extensive retinal pigmentary derangement.

Although the extent of optic disc pallor and peripheral pigmentary alterations may vary, patients with retinitis pigmentosa invariably have retinal vascular attenuation. The presence of mild vitreous cells is common.

The characteristic peripheral pigmentary changes are described as “bone spicules.” The bone spicules are most prominent in the midperipheral retina.

Loss of visual acuity may result from posterior subcapsular cataracts or cystoid macular edema (CME). The CME is characterized by a petaloid pattern of hyperfluorescence in the fovea.

Optic nerve drusen may be observed in patients with retinitis pigmentosa.

SORSBY’S FUNDUS DYSTROPHY

Sorsby’s fundus dystrophy is a progressive maculopathy inherited as an autosomal dominant trait. Patients usually experience the onset of symptoms in the third or fourth decade of life.

Symptoms

Persons affected typically experience loss of central vision and nyctalopia.

Clinical Features

During the early stages of this progressive maculopathy, confluent plaques are observed at the posterior pole beneath the retinal pigment epithelium (RPE). As the disease progresses, choroidal neovascularization develops. The maculopathy evolves into geographic atrophy, subretinal fibrosis, and pigment clumping.

Ancillary Testing

Color vision testing may reveal a tritan color defect in the early stages of the disease. This feature is useful for identifying individuals with this condition but with a normal-appearing fundus. Visual field testing typically shows a central scotoma that may increase as a result of progression of atrophy into the peripheral retina. Fluorescein angiography reveals a delay in choroidal filling. Choroidal neovascularization is manifested by hyperfluorescence and leakage in fluorescein angiography. The electroretinogram and electro-oculogram findings are typically normal in the initial stages of this maculopathy. Dark adaptation becomes affected in the late stages, showing a delayed or absent cone-rod break.

Pathology/Pathogenesis

Histopathologic studies have shown thickening of Bruch’s membrane secondary to lipid deposition between the RPE basement membrane and the inner collagenous zone. The gene for Sorsby’s fundus dystrophy has been mapped to 22q12.1-q13.2, which codes for a tissue inhibitor of metalloproteinase-3. This gene product is necessary for the extracellular matrix remodeling process. Hence, mutations in this gene lead to changes in the extracellular matrix milieu affecting Bruch’s membrane.

Treatment/Prognosis

Sorsby’s fundus dystrophy has a poor prognosis, because atrophy and scarring may extend into the periphery as the condition evolves. Patients may have severely affected nonambulatory vision. In a clinical study, administration of high doses of vitamin A was associated with an improvement of symptoms and retinal functional tests in affected patients. However, no treatment has been established for this condition, and further investigations are necessary.

Systemic Evaluation

There are no known systemic associations with Sorsby’s fundus dystrophy.

Sorsby’s fundus dystrophy is associated with subretinal fibrosis, retinal pigment epithelial atrophy, and pigment clumping throughout the macula.

Seven years later, the patient shown in the previous figures had more extensive subretinal fibrosis, retinal pigment epithelial atrophy, and pigment plaques. Subretinal hemorrhage and fluid were also observed.

This patient had bilateral, symmetric macular abnormalities, which is characteristic of Sorsby’s fundus dystrophy.

The progression of her macular abnormalities was evident bilaterally. Her left eye showed extensive abnormalities extending beyond the macula to the superior and nasal retina.