CONGENITAL STATIONARY NIGHT BLINDNESS

Congenital stationary night blindness (CSNB) is a group of diseases characterized by nonprogressive night blindness. The diseases are classified as CSNB with normal fundus and CSNB with fundus abnormality. The CSNB with normal fundus can be further divided in three subtypes based on hereditary patterns: autosomal recessive, autosomal dominant, and X-linked. The CSNB variety with fundus abnormality includes Oguchi disease (autosomal recessive), fundus albipunctatus (autosomal recessive), and the flecked retina of Kandori.

Symptoms

Vision in autosomal dominant CSNB usually is normal, while in the autosomal recessive form of CSNB it may be normal or moderately decreased. Individuals with the X-linked form of CSNB may have poor vision; nevertheless, they usually do not complain of nyctalopia. In Oguchi disease and fundus albipunctatus, affected persons have normal vision and problems with dark adaptation. Flecked retina of Kandori is characterized by normal visual acuity and less impairment of night vision.

Clinical Features

Autosomal dominant CSNB, autosomal recessive CSNB, and X-linked CSNB are characterized by a normalappearing fundus. Patients with the autosomal recessive and X-linked forms are likely to be myopic. Nystagmus is part of the clinical findings of X-linked CSNB. The retinal appearance of individuals with Oguchi disease shows a yellowish sheen after light exposure. After several hours of dark adaptation, the retina looks normal (Mizuo-Nakamura phenomenon). The retinal findings of fundus albipunctatus consist of white-yellow dots scattered in the posterior pole (sparing the macula) and radiating toward the midperiphery and retinal vessels of normal caliber. The flecked retina of Kandori shows large flecks in the equatorial zone.

Ancillary Testing

Dark adaptometry studies reveal delayed or poor rod adaptation and elevated final thresholds. The CSNB with normal fundus demonstrates two electroretinogram (ERG) patterns. The negative ERG (SchubertBornschein), which is the most common pattern, consists of a normal scotopic a-wave and a reduced or absent scotopic b-wave. This pattern can be seen in autosomal recessive and X-linked CSNB. The negative ERG pattern can be further classified into a complete type (rod function is almost absent) or incomplete type (moderate rod function). In the second ERG pattern (Riggs), the

amplitudes of both scotopic a- and b-waves are reduced. This ERG pattern is usually characteristic of autosomal dominant CSNB. The ERG in Oguchi disease has a normal a-wave and a reduced b-wave under scotopic conditions with persistence of this abnormal response after prolonged dark adaptation. Fundus albipunctatus has elevated dark adaptation thresholds, and the ERG becomes normal with dark adaptation.

Pathology/Pathogenesis

Several mutational defects have been identified as the cause of CSNB. For autosomal dominant CSNB, three loci have been mapped: 3p22 (gene product is an alpha subunit of rod transducin), 3q21-q24 (rhodopsin gene), and 4p16.3 (beta subunit of rod cyclic guanosine monophosphate [cGMP] phosphodiesterase). The complete type of x-linked CSNB has been mapped to Xp11.4. The gene encodes nyctalopin (leucine-rich protein expressed in the retina and brain). The incomplete type has been mapped to Xp11.23. A defect in the process of pigment regeneration is the underlying etiology of fundus albipunctatus, whereas in Oguchi disease the pigment regeneration is not affected. Oguchi disease has a mutation in 2q37.1 (arrestin gene), and prolonged stimulation of photoreceptors by light is a possible explanation of the clinical findings.

Treatment/Prognosis

There is no known treatment for this group of disorders. Fortunately, these conditions are stationary.

Systemic Evaluation

No systemic associations have been described with CSNB.

Individuals with congenital stationary night blindness may have a normal-appearing fundus.

Oguchi disease is characterized by an unusual yellowish sheen of the fundus following light exposure.

The scotopic electroretinogram in those with congenital stationary night blindness may demonstrate a normal a-wave and a reduced or absent b-wave.

Fundus photograph of the fellow eye of the patient in the previous figure demonstrates the same yellowish sheen. After several hours of dark adaptation, the retina may appear normal (Mizuo-Nakamura phenomenon).

Fundus albipunctatus is characterized by numerous white-yellow dots scattered throughout the retina. The macula is usually spared.

Patients with fundus albipunctatus have normalappearing optic discs and retinal vessels (in contrast to patients with retinitis punctata albescens).

DOMINANT DRUSEN

Dominant drusen, also known as Doyne’s honeycomb dystrophy, malattia leventinese, Hutchinson-Tay choroiditis, and Holthouse-Batten superficial chorioretinitis, is a dominantly inherited macular disorder. The onset of macular drusen occurs in the second to third decades.

Symptoms

Affected patients usually have good visual acuity despite the presence of multiple drusen. Drusen are initially evident during the third decade of life. In the late stages of the disease, the central vision becomes affected. Patients may complain of metamorphopsia and central scotomas.

Clinical Features

This disorder is characterized by multiple, small round or elongated drusen in the posterior pole extending beyond the arcades and involving retina nasal to the optic nerve head. As the disease progresses, the drusen may become confluent. Subretinal fibrous metaplasia and retinal pigment epithelial (RPE) and choriocapillaris atrophy may be observed. Choroidal neovascularization rarely may occur.

Ancillary Testing

Fluorescein angiography shows hyperfluorescent dots corresponding to drusen. Often fluorescein angiography reveals more drusen and RPE atrophy than are evident clinically. Findings of electroretinogram, dark adaptation, and electro-oculogram are usually normal. Visual field testing may reveal central scotomas. In the late stages of the disease a red-green dyschromatopsia may be evident.

Pathology/Pathogenesis

Dominant drusen is inherited as an autosomal dominant disorder. The genetic defect causing dominant drusen (EFEMP1) has been mapped to 2p16-p21. A single mutation (Arg345Trp) has been identified in all affected patients. The genetic defect is a defective extracellular matrix protein that leads to a defective basement membrane. Histopathologic studies reveal thickening of the basement membrane of the RPE. In the late stages of the condition, the retina and choroid may be atrophied.

Treatment/Prognosis

Patients affected with dominant drusen usually have good visual acuity in spite of their clinical findings. Central vision may become affected gradually as the disease progresses. Nevertheless, visual loss may occur as a result of choroidal neovascularization. Fortunately, this complication is rare.

Systemic Evaluation

Certain hereditary renal conditions with underlying basement membrane anomalies like Alport’s syndrome and glomerulonephritis type II may be associated with drusen-like deposits in the retina.

Dominant drusen is characterized by multiple, small round or oval deposits at the level of the retinal pigment epithelium.

This young man had confluent macular drusen surrounded by a radial pattern of fine drusen deposits.

The drusen are most common in the posterior pole but may extend beyond the vascular arcades and involve the retina nasal to the optic nerve head.

Fluorescein angiography reveals innumerable hyperfluorescent spots corresponding to the drusen.

Some patients with dominant drusen may develop subretinal fibrous metaplasia.

The fellow eye of the patient in the previous figure demonstrates the symmetric nature of dominant drusen.

GYRATE ATROPHY

Gyrate atrophy is an autosomal recessive chorioretinal dystrophy. Most patients become aware of symptoms in the second or third decade of life.

Symptoms

Affected patients present with night blindness and progressive peripheral visual loss in their second or third decade. Central vision is preserved until later in life. Color vision remains unaffected until the later stages of the condition. This dystrophy is characterized by a slowly progressive course.

Clinical Features

Fundus findings consist of focal areas of midperipheral chorioretinal atrophy. These areas eventually enlarge and coalesce, spreading toward the macula and peripherally. These atrophic regions have characteristic scalloped borders, creating a contrast between normal and abnormal retinal pigment epithelium. Extensive choroidal atrophy and pigment clumping as well as optic disc pallor and narrowing of the retinal vessels are evident in the late stages of the disease. Most individuals with gyrate atrophy have high myopia, astigmatism, and posterior subcapsular cataracts.

Ancillary Testing

Fluorescein angiography reveals absence of the choriocapillaris in the affected zones. The junction between choriocapillaris atrophy and normal choriocapillaris flush of unaffected tissues is hypofluorescent because of pigment accumulation.

The electro-oculogram (EOG) is abnormal in gyrate atrophy. The electroretinogram (ERG) demonstrates reduced rod and cone responses during the early stages in spite of minimal findings. With further progression of the condition, the ERG becomes extinguished.

Patients with gyrate atrophy have high levels of ornithine in serum, urine, and cerebrospinal fluid.

Pathology/Pathogenesis

The genetic mutation of this condition involves a deficiency of the enzyme ornithine aminotransferase. This pyridoxal phosphate-dependent enzyme is involved in ornithine metabolism. The gene coding for ornithine aminotransferase has been mapped to 10q26. Histopathologic study of eyes of a patient with vitamin B6- responsive gyrate atrophy revealed areas of focal atrophy of the retinal pigment epithelium (RPE) and photoreceptors in the posterior pole. There was an abrupt transition from normal retina to almost absolute atrophy of the retina, RPE, and choroid.

Treatment/Prognosis

Some studies have shown a slower progression of the condition, with treatment aimed toward reducing ornithine levels. Lowering of plasma ornithine levels can be accomplished with a restricted intake of arginine as well as with vitamin B6 administration. Nonetheless, different results have been reported with these treatment modalities.

Systemic Evaluation

Several associated systemic findings have been reported. These include ultrastructural changes in skeletal muscle fibers, enlarged mitochondria in hepatic cells, atrophic white matter lesions detected on brain magnetic resonance imaging, and abnormal findings on electroencephalography.

The fundus findings in patients with gyrate atrophy include midperipheral chorioretinal atrophy that spreads toward the macula and periphery.

The stage of chorioretinal atrophy in patients with gyrate atrophy is relatively uniform in all affected areas.

The atrophic areas have well-defined, scalloped borders. The areas between the atrophic patches may be hyperpigmented. Serum ornithine levels are elevated as a result of ornithine aminotransferase deficiency.

Pigment clumps may be visible within areas of chorioretinal atrophy.

In the late stages of gyrate atrophy, the optic discs are pale and the retinal vessels are attenuated.

Extensive chorioretinal atrophy reveals the underlying sclera in advanced cases.

LEBER’S CONGENITAL AMAUROSIS

Leber’s congenital amaurosis is a congenital retinal disorder inherited as an autosomal recessive trait. Patients affected with this condition usually present with the clinical picture at birth.

Symptoms

Children affected with Leber’s congenital amaurosis experience poor vision and photophobia. Most patients have nystagmus. It is not unusual for patients to continuously push or rub their eyes (oculodigital sign or reflex).

Clinical Features

The clinical picture of patients with Leber’s congenital amaurosis includes very poor visual acuity, nystagmus, sluggish pupillary reflexes, hyperopia, and a positive oculodigital reflex. The majority of children with Leber’s congenital amaurosis have a normal-appearing fundus. However, some patients may present with pigmentary changes, optic nerve pallor, and vessel attenuation. Keratoconus and cataracts can be associated findings in older children with this condition.

Ancillary Testing

Electroretinographic testing plays a pivotal role in establishing the diagnosis. Patients affected with this disorder have a severely abnormal or undetectable electroretinogram. This feature is helpful to distinguish Leber’s congenital amaurosis from other conditions that can mimic it in certain ways.

Pathology/Pathogenesis

Mutations in different genes have been associated with Leber’s congenital amaurosis. Mutational defects at locus 1p31, which gene product is a 65-kD retinal pigment epithelium (RPE) protein, can be associated with this disorder. Mutations in a gene encoding for a retinalspecific guanylate cyclase (17p13.1), which is involved in the phototransduction process, can be associated with Leber’s congenital amaurosis (LCA). Defects in the arylhydrocarbon-interacting receptor protein-like 1 gene at 17p13.1, at 6q11-q16, and at 14q24 loci may account for some LCA cases. Histopathologic studies have shown loss of photoreceptors, gliosis, degeneration of retina and RPE, and intraretinal pigment migration.

Treatment/Prognosis

Unfortunately, there is no treatment for Leber’s congenital amaurosis. This disease is a retinal dysgenesis in which a progression of retinal changes is unlikely to greatly affect the level of visual acuity. Decrease of visual acuity can result from keratoconus, macular colobomas, or cataract formation.

Systemic Evaluation

The term Leber’s congenital amaurosis implies no associated systemic findings. Some cases of mental or psychomotor retardation have been reported in association with the disease. Nevertheless, some authors have argued that this feature is secondary to visual deprivation.

The majority of patients with Leber’s congenital amaurosis have normal-appearing retinas. However, extensive pigmentary abnormalities may be observed.

This 6-year-old boy had a history of poor vision since birth. Fundus photograph of his right eye reveals diffuse mottling of the retinal pigment epithelium with a “salt and pepper’’ stippling of the retina.

This patient has extensive retinal pigmentary alterations but normal-appearing optic discs and retinal vessels.

The same patient’s left eye had similar findings, demonstrating the symmetric nature of the retinal alterations in Leber’s cogenital amaurosis.