CHAPTER 11
Congenital and Stationary Retinal Disease
Color Vision (Cone System) Abnormalities
Color vision defects can be congenital or acquired. Congenital color vision defects are stationary and usually affect both eyes equally, whereas acquired defects may be progressive and may be uniocular, depending on the underlying cause.
Congenital Color Deficiency
Trichromacy
Congenital color vision defects are traditionally classified by an individual’s color-matching performance. A person with normal color vision (trichromatism, or trichromacy) can match any colored light by varying a mixture of 3 different-colored lights, or primary colors (eg, a longwavelength red, middle-wavelength green, and short-wavelength blue light).
Individuals with anomalous trichromatism make up the largest group of color-deficient persons; they include approximately 5%–6% of males. These individuals also can use 3 primary colors to match a given color, but because one of their cone photopigments has an abnormal absorption spectrum, they use different proportions of colors from those used by persons with normal color vision. For approximately 5% of males, the medium-wavelength (M-cone) photopigment has an abnormal absorption spectrum that is closer to that of the long-wavelength (L-cone) photopigment, a condition known as deuteranomalous trichromatism. For 1% of males, the L-cone photopigment has an absorption spectrum that is closer to that of the M-cone photopigment, termed protanomalous trichromatism. Congenital tritanomalous defects are even rarer than tritanopic defects (described in the next section), and some specialists question whether such defects exist.
Anomalous trichromacy ranges in severity. Some individuals have only a mild abnormality and may, for example, fail some of the sensitive Ishihara test plates but have no trouble naming colors or passing the less-sensitive screening tests such as the Farnsworth Panel D-15 test (see Chapter 3). Others have poor color discrimination and may appear to have dichromacy on some of the color vision tests.
Hereditary congenital color vision defects are most frequently X-linked-recessive, red-green abnormalities; they affect 5%–8% of males and 0.5% of females. Acquired defects are more frequently of the blue-yellow, or tritan, variety and affect males and females equally. Table 11-1 shows the traditional classification of color vision deficits on the basis of color-matching test results.
Table 11-1
Dichromacy
Individuals who need only 2 primary colors to make a color match have dichromacy. It is assumed that such individuals lack one of the cone photopigments. Approximately 2% of males have dichromacy; 1% are missing the long-wavelength (L-cone) photopigment, a disorder termed protanopia, and 1% are missing the medium-wavelength (M-cone) photopigment, called deuteranopia. A rare, third form of congenital dichromacy is lack of the short-wavelength (S-cone) photopigment, termed tritanopia, which is an autosomal-dominant defect that occurs in approximately 0.001% of the population.
Achromatopsia
An absence of color discrimination, or achromatopsia, means that any spectral color can be matched with any other solely by intensity adjustments. The congenital achromatopsias are disorders of photoreceptor function. Essentially, there are 2 forms of achromatopsia: (1) rod monochromatism, and (2) S-cone monochromatism (blue-cone monochromatism). Both disorders typically present with congenital nystagmus, poor visual acuity, and photophobia. Electroretinography (ERG) enables the distinction from congenital motor nystagmus or ocular albinism, both of which are associated with normal cone ERGs (see Chapter 3, Fig 3-2).
Rod monochromatism (complete achromatopsia) is the most severe form; affected individuals have normal rod function but no detectable cone function and see the world in shades of gray. Patients may have full to partial expression of the disorder, with visual acuity ranging from 20/80 to 20/200. Nystagmus is usually present in childhood and may improve with age. Characteristically, the ERG in patients with rod monochromatism shows an absence of cone-derived responses and normal rod responses. Dark adaptometry shows no cone plateau and no cone–rod break. The disorder exhibits autosomal-recessive inheritance.
As of mid-2014, 5 genes had been identified that are associated with the disorder: (1) CNGA3, on 2q11, which accounts for 20%–30% of cases and encodes the alpha subunit of the cone photoreceptor cyclic guanosine monophosphate (cGMP)–gated cation channel; (2) CNGB3, on 8q21–q22, which accounts for 40%–50% of cases and encodes the beta 3 subunit of the cGMP-gated cation channel;
(3) GNAT2, on 1p13.3, which encodes the alpha subunit of cone-specific transducin; (4) PDE6 C, on 10q23.33, which encodes cGMP-specific cone phosphodiesterase 6C alpha protein; and (5) PDE6H, on 12p13, which encodes the inhibitory γ subunit of the cone photoreceptor cGMP phosphodiesterase. The latter 3 genes account for less than 5% of cases.
In S-cone (or blue-cone) monochromatism, rods and S cones are normal, but L- and M-cone function is absent. The condition is usually X-linked and can be difficult to distinguish clinically from
rod monochromatism in the absence of a family history or results of specialized color or ERG testing. Persons with S-cone monochromatism exhibit preserved S-cone ERG responses, severely reduced cone flicker ERGs, and normal rod ERGs; they typically have a visual acuity of approximately 20/80, which is better than that in typical rod monochromatism.
Dingcai C. Color vision and night vision. In: Ryan SJ, Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, eds. Retina. Vol 1. 5th ed. Philadelphia: Elsevier/Saunders; 2013:285–299.
Wu DM, Amani AF. Abnormalities of cone and rod function. In: Ryan SJ, Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, eds. Retina. Vol 2. 5th ed. Philadelphia: Elsevier/Saunders; 2013:899–906.
Night Vision (Rod System) Abnormalities
Congenital Night-Blinding Disorders With Normal Fundi
Congenital stationary night blindness (CSNB) is a nonprogressive disorder of night vision. Three genetic subtypes have been described:
1.X-linked, the most common
2.autosomal recessive
3.autosomal dominant (rare), typified by the large French Nougaret pedigree
Snellen visual acuities of patients with CSNB range from normal to occasionally as poor as 20/200, but most cases of decreased vision are associated with significant myopia. The fundus is usually normal, with the exception of myopic changes. Difficulty with night vision is the common presenting symptom, but nystagmus and reduced visual acuity may also be presenting symptoms. Although dark-adaptometry curves are typically 2–3 log10 units above normal, some CSNB patients never complain of nyctalopia, perhaps because they have become accustomed to it as a way of life (Fig 11-1).
Figure 11-1 Dark-adaptometry curve in congenital stationary night blindness (CSNB). The dark-adaptometry curve of this patient (dotted curve) with CSNB shows no rod adaptation. Dashed curve indicates normal response. (Used with permission from Ripps H. Night blindness revisited: from man to molecules. Proctor lecture. Invest Ophthalmol Vis Sci. 1982;23(5):588–609.)
Electroretinography is important in the diagnosis of CSNB. The most common ERG pattern is the negative ERG (the Schubert-Bornschein form of CSNB), in which the bright-flash, dark-adapted ERG
has a normal (or near-normal) a-wave but a markedly reduced b-wave. The normal a-wave excludes significant rod photoreceptor dysfunction, and the result thus facilitates the distinction of CSNB from the potentially blinding disorder retinitis pigmentosa (RP; see Chapter 3).
X-linked CSNB has been categorized into 2 types: “complete” and “incomplete.” Patients with the complete type (cCSNB) have an undetectable rod-specific, dim-flash, dark-adapted ERG and psychophysical thresholds that are mediated by cones. Patients with incomplete CSNB (iCSNB) have some detectable rod function on ERG and an elevated dark-adaptation final threshold. Subsequently, advances in molecular biology have shown the 2 forms to be genetically distinct; X-linked cCSNB is associated with a mutation in NYX and X-linked iCSNB with a mutation in CACNA1F. NYX encodes nyctalopin, a protein required for normal synaptic transmission between retinal photoreceptors and depolarizing (on-) bipolar cells. The ERG findings are those of panretinal loss of on-bipolar cell function in rods and in all 3 cone types. Cone off-bipolar cell function is spared (Fig 11-2). CACNA1F encodes a transmembrane protein that functions as an alpha-1 subunit of the voltagedependent calcium channel, and functions of both onand off-pathways are affected (see Fig 11-2). Standard cone-system ERGs in iCSNB are therefore more abnormal than those in cCSNB (see Chapter 3, Fig 3-2).
Figure 11-2 Electroretinography (ERG) patterns of onand off-responses in CSNB. The stimulus has a 200-millisecond (ms) duration to enable independent recording of the ERG responses to onset and offset. A, The pattern of a patient with “complete” CNSB shows a negative-waveform on-response but a normal off-response. B, A patient with “incomplete” CSNB shows both onand off-response abnormalities. C, Pattern of a normal subject. (See also Chapter 3, Fig 3-2.)
(Courtesy of Graham E. Holder, PhD.)
The ERG categories of cCSNB and iCSNB also apply to the autosomal-recessive forms of CSNB. The most common causes of recessive cCSNB are mutations in GRM6 or TRPM1. Other genes implicated in recessive cCSNB include GPR179 and LRIT3. An identical pattern also occurs in melanoma-associated retinopathy (MAR), a paraneoplastic autoimmune retinopathy that can develop in patients with cutaneous malignant melanoma, emphasizing the need always to place ERG responses in their clinical context. MAR patients usually present with an acquired night blindness and shimmering photopsias; CSNB patients are night-blind from birth. In at least some patients, MAR is mediated through TRPM1 (transient receptor protein member 1), which is expressed in melanocytes and retinal on-bipolar cells. A recessive form of iCSNB relates to mutation in CABP4.
Congenital Night-Blinding Disorders With Fundus Abnormality
Fundus albipunctatus relates to mutation in RDH5 (12q13–q14). RDH5 encodes 11-cis-retinol dehydrogenase, a microsomal enzyme in the retinal pigment epithelium (RPE) that converts 11-cis- retinol into 11-cis-retinal and is therefore involved in the regeneration of rhodopsin. Patients have very delayed rhodopsin regeneration, and although levels eventually normalize, the process may take many hours in the dark. Accordingly, many ERG testing laboratories practice overnight dark adaptation of 1 eye in appropriate patients. Affected individuals are night blind from birth and usually exhibit yellow-white dots in the posterior pole (sparing the fovea) that extend into the midperiphery (Fig 11-3). ERG responses commonly show a cone-isolated retina pattern, with undetectable rodspecific ERG, and a severely reduced bright-flash dark-adapted ERG (arising in dark-adapted cones) that normalizes with sufficiently extended dark adaptation. Patients with a normal fundus but characteristic ERG findings and molecular confirmation of the mutation have been described; visual acuity and color vision are usually good.
Figure 11-3 Fundus photograph of a patient with fundus albipunctatus, showing multiple spots of unknown material scattered primarily throughout the deep retina. (From Fishman GA, Birch DG, Holder GE, Brigell MG. Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway. Ophthalmology Monograph 2. 2nd ed. San Francisco: American Academy of Ophthalmology; 2001:51.)
Fundus albipunctatus must be distinguished from retinitis punctata albescens, a disorder related to mutation in RLBP1, which encodes cellular retinaldehyde-binding protein. The condition is a progressive rod–cone dystrophy. The white dots may be finer than those of RDH5 retinopathy, and there may be attenuation of the retinal vessels. ERG responses are usually very abnormal and show some recovery with extended dark adaptation but do not normalize.
Oguchi disease is also associated with night blindness from birth. It results from mutation in the gene SAG (2q37), which encodes arrestin, or in GRK1 (13q34), which encodes rhodopsin kinase. This very rare disorder is most common in Japanese patients. The fundus in Oguchi disease is normal after dark adaptation but shows a peculiar yellow iridescent sheen after even brief light exposure (the
Mizuo-Nakamura phenomenon; Fig 11-4).
Figure 11-4 The Mizuo-Nakamura phenomenon. The fundus of this patient with X-linked cone dystrophy is unremarkable in the dark-adapted state (right) but has a yellow iridescent sheen after exposure to light (left).
Cukras CA, Zein WM, Caruso RC, Sieving PA. Progressive and “stationary” inherited retinal degenerations. In: Yanoff M, Duker JS, eds. Ophthalmology. 4th ed. St. Louis: Elsevier/Saunders; 2013:480–490.
Dryja TP. Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness. LVII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2000;130(5):547–563.