Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture☆

Article Outline

• Abstract
• Diagnosis of night blindness
• The dark-adaptation curve
• Electroretinography
• The phototransduction cascade
• Rhodopsin and dominant stationary night blindness
• The alpha subunit of rod transducin and the nougaret form of stationary night blindness
• The beta subunit of rod cGMP-phosphodiesterase and the rambusch form of stationary night blindness
• Rhodopsin kinase, arrestin, and Oguchi disease
• 11-cis retinol dehydrogenase (11-cis rdh) and fundus albipunctatus
• A retinal L-type calcium channel and the incomplete form of X-linked stationary night blindness
• Conclusion
• Acknowledgements
• References
• Copyright

Abstract 

PURPOSE: To compare the clinical findings of the various forms of stationary night blindness caused by mutations in identified genes encoding proteins of photoreceptors or the retinal pigment epithelium.

METHODS: Review of the visual acuities, visual fields, fundi, dark-adaptation curves, and electroretinograms from patients with stationary night blindness caused by mutations in the genes RHO, GNAT1, PDE6B, RHOK, SAG, RDH5, and CACNA1F, respectively encoding rhodopsin, the α subunit of rod transducin, the β subunit of rod cGMP-phosphodiesterase, rhodopsin kinase, arrestin, 11-cis retinol dehydrogenase, and a retinal L-type calcium channel.

RESULTS: In the evaluated forms of stationary night blindness, the time course of dark adaptation and the characteristics of the electroretinogram indicate that rod photoreceptors are present and that they function, although abnormally. In night blindness resulting from defects in rhodopsin, the α subunit of rod transducin, or the β subunit of rod cGMP phosphodiesterase, rod photoreceptors respond only to light intensities far brighter than normal, and the sensitivity of rods to light is similar to that of normal individuals who are not dark adapted. In fundus albipunctatus and in Oguchi disease, the rod photoreceptors can achieve normal sensitivity to dim light but only after 2 or more hours of dark adaptation, compared with approximately 0.5 hours for normal individuals. In each of these forms of stationary night blindness, the poor rod sensitivity and the time course of dark adaptation correlate with the known or presumed physiologic abnormalities caused by the identified gene defects. Patients with some forms of stationary night blindness, such as fundus albipunctatus and Oguchi disease, may develop degeneration of the retina leading to severe loss of vision in later life.

CONCLUSIONS: The identification of the mutant genes causing forms of stationary night blindness refines the classification of these diseases and enhances our understanding of the underlying physiologic defects. Ophthalmologists must be aware that although these diseases are traditionally categorized as “stationary,” some of them lead to reduced visual acuity or constricted visual fields, especially in older patients. Efforts to develop therapies for these diseases should concentrate on these more severe forms.

Ivividly recall my first exposure to the Edward Jackson Memorial Lecture. During my residency in ophthalmology 20 years ago, I made up my mind to spend a few postresidency years in a research laboratory. I chose to investigate retinoblastoma using the exciting new technology called “recombinant DNA,” which is now referred to as “molecular genetics.” I believe I was as thrilled with the notion of learning this new technology as with the possibility of finding the gene that caused this hereditary cancer. But first I spent weeks in the libraries at Harvard learning as much as I could about retinoblastoma. During that literature search, I came across a very clearly written and instructive review of retinoblastoma, its genetics, and its history. This was not an article to skim over; I read it word for word. It was the Jackson Lecture that Edwin Dunphy gave in 1963.1 I hope that my Jackson lecture will cover the topic I have selected in a comparably scholarly manner.

The molecular genetics techniques that proved so powerful in identifying and characterizing the retinoblastoma gene in the 1980s have been used by my laboratory in the 1990s to identify many genes causing hereditary degenerations of the retina, such as retinitis pigmentosa. Alan Bird’s 1994 Jackson Lecture covers some of the advances in our understanding of the genes causing retinitis pigmentosa. What is not available in the recent literature is a summary of our new knowledge about stationary night blindness. Many ophthalmologists do not pay much attention to forms of stationary night blindness, perhaps because they are uncommon, because their underlying physiology has been mysterious, and because they are generally considered “mild” diseases not leading to loss of photopic (daytime) vision. My review of Edward Jackson’s bibliography failed to find a single article by Dr Jackson dealing with this topic. However, ophthalmologists may delight in learning that the identification of the genetic defects causing some of these conditions has removed much of the mystery behind their physiology. There are consistent differences between the genetically defined forms of stationary night blindness in the time course of dark adaptation and the degree of insensitivity of the retina to dim light, and these distinguishing features logically correlate with the underlying gene defects. It is now possible to reliably group together young and old patients from different families with the same gene defects. Evaluating such groups of patients has provided firm evidence that some of these diseases must now be recategorized as “progressive” photoreceptor degenerations that lead to severe, permanent loss of vision.

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Diagnosis of night blindness 

A century ago, night-blind individuals were handicapped at night. They hurried home at the approach of dusk, and, if caught outside at night, they walked with “head erect, arms extended, and hands open.”2 The situation is very different today. With ubiquitous electric illumination, we are able to see in color (that is, we use our cones) throughout the night; rods are no longer essential for many nighttime activities. Patients with night blindness may not complain of their condition. They may not even recognize the problem, minimizing the trouble seeing in dimly lit restaurants or movie theaters and believing it to be comparable to the difficulty normally sighted individuals have when they suddenly go from a brightly lit environment to a dark one. Patients with Oguchi disease or fundus albipunctatus, in which rods ultimately become fully sensitive to dim illumination after a few hours of dark adaptation, are the ones most likely to be unaware of their disease. Other patients may deny their condition or may hide its existence to retain the ability to drive at night. One well-documented patient entered military service and became a sergeant during World War II. His night blindness was not diagnosed until he wrecked a truck during blackout maneuvers.3

Ophthalmologists may mistakenly consider some patients who do report trouble with vision at night to be malingerers or hysterics. The symptom is ignored because normal visual acuity may be recorded with standard tests. One must remember that Snellen-chart measures of visual acuity test the function of the foveola, where there are only cones. Specific tests for rod function, such as scotopic electroretinograms and dark-adaptation plots, are usually not performed. It is especially important to correctly diagnose young patients with night blindness because it may be the first symptom of a progressive degeneration of the retina, such as retinitis pigmentosa. Making the correct diagnosis is important also because patients must be counseled against certain nighttime activities, such as driving at night.

The differential diagnosis of night blindness is summarized in Table 1. I will not cover the acquired forms of night blindness listed in the table, except to make note of the night blindness caused by dietary deficiency of vitamin A. The diagnosis of this condition is crucial to the affected patients, because prompt therapy with vitamin A can reverse the condition and prevent permanent retinal degeneration.4, 5, 6, 7, 8 Nor will I review retinitis pigmentosa and allied forms of progressive retinal degeneration, which can present with early-onset night blindness. Rather, I will discuss hereditary forms of congenital stationary night blindness, particularly those types for which the responsible genetic defects have been identified.

TABLE 1. Differential Diagnosis of Night Blindness

A number of features have been used to classify patients with congenital stationary night blindness. Forms of this condition differ in their inheritance pattern (autosomal dominant, autosomal recessive, or X linked), electroretinograms (for example, presence versus absence of the rod a-wave), refractive error (presence or absence of myopia), and fundus appearance (for example, the Mizuo-Nakamura phenomenon in Oguchi disease or the white dots in fundus albipunctatus). However, many of the classical diagnostic categories that were based on these clinical features do not specify distinct diseases. For example, the Schubert-Bornschein type of night blindness,9 characterized by the presence of a rod a-wave and markedly decreased rod b-wave, is usually but not always associated with myopia, is usually X-linked but can also be autosomal recessive, and the X-linked forms are further divided into two subtypes, complete and incomplete,10 based on whether a rod b-wave is present with certain electroretinogram test conditions. Another example is the Riggs type of stationary night blindness, the designation for patients with a normal fundus and no rod a-wave.11 Some patients with the electroretinogram of the Riggs type of stationary night blindness come from families with an autosomal dominant inheritance pattern, and these have sometimes been referred to as having the Nougaret type, eponymously labeled after the founder of a large family with dominant stationary night blindness originating in southern France.12, 13, 14 However, not all Riggs-type cases with dominant inheritance have a defect in the same gene, so the name “Nougaret type” should probably be reserved for those with the gene defect found in the Nougaret family (see section on the α subunit of rod transducin below). The recessively inherited Riggs types are likely to be genetically distinct from any of the dominantly inherited forms. To improve the diagnostic precision, I will classify forms of night blindness according to their causative genes. The classification is not complete, because the genes causing some forms of night blindness are still unknown. Nevertheless, the categories that are established should be enduring and unambiguous. I have grouped the genetically defined categories according to the inheritance patterns (Table 2).

TABLE 2. Mutant Genes Causing Congenital Stationary Night Blindness

All patients with stationary night blindness have an abnormal dark-adaptation curve and an abnormal electroretinogram. Because these tests of photoreceptor function are so crucial to the diagnosis and characterization of night blindness, I will briefly describe them.

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The dark-adaptation curve 

After exposure to bright light for a time sufficient to bleach 25% or more of the rhodopsin in the retina, normal rods are insensitive to light and cones respond only to very bright stimuli. A subject’s subsequent recovery of light sensitivity can be monitored by placing the subject in the dark and periodically presenting spots of light of varying intensity in the visual field and asking the subject if they are perceptible. A plot of the light intensity of a minimally perceptible spot versus time is called the dark-adaptation curve (Figure 1). In the first 5 to 10 minutes of darkness, the sensitivity of the retina rapidly improves approximately 1000-fold (3 log₁₀ units). This early recovery is mediated by the cone mechanism and is called the cone branch of the dark-adaptation curve. (The term “cone mechanism” refers to cones and their associated bipolar cells and higher-order neurons considered together as a functional unit.) Rod photoreceptors are also recovering during this time, but more slowly. A few minutes after cones achieve their maximum sensitivity, the “rod-cone break” occurs; this is when rods become perceptibly more sensitive than cones. The sensitivity of the rod mechanism continues to improve; this is referred to as the rod branch of the dark-adaptation curve. After another 15 to 30 minutes, the fully dark-adapted rods allow the subject to see spots of light over 100 times (over 2 log₁₀ units) dimmer than would be possible with cones alone.

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• Figure 1. 

  Schematic dark-adaptation curves in normal individuals and in patients with stationary night blindness. In all three graphs, the y axis is the minimal intensity of a perceptible spot of light (logarithmic scale, units are microapostilbs) at the time (minutes) designated on the x axis after exposure to light that bleaches 25% or more of the rhodopsin in each rod photoreceptor. The solid curve in each panel represents the normal dark-adaptation curve. The top left graph has the normal curve labeled with its components: the initial cone branch which ends at the rod-cone break and is followed by the rod branch. (Top left) The dark-adaptation curves found in patients with the Nougaret or Rambusch forms of dominant stationary night blindness (which are very similar and are represented by a single dashed line)27, 29 and in a patient with the dominant rhodopsin mutation Ala292Glu causing stationary night blindness (dotted line, based on unpublished observations of Drs. Berson and Sandberg). (Top right) Dark-adaptation curves from patients with complete (dashed line) or incomplete (dotted line) X-linked stationary night blindness (XL-SNB).10 (Bottom) Dark-adaptation curves characteristic of fundus albipunctatus53 (dashed line) and Oguchi disease36, 38 (dotted line). The rod-cone break in both fundus albipunctatus and Oguchi disease has been arbitrarily placed at the 2-hour time point; in reality, it could be somewhat before or after this time point depending on the degree of light exposure preceding the evaluation of dark adaptation.

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Electroretinography 

Standard electroretinograms are performed in patients with pharmacologically dilated pupils and after full dark adaptation of the retina (that is, approximately 30 to 40 minutes). The electroretinogram is measured noninvasively with a contact lens electrode placed on the cornea, and it is recorded with corneal voltage on the y axis and time on the x axis. The response to a brief (usually less than 0.1 ms) flash of light (Figure 2) is divided into components or “waves.” The a-wave is a fast, cornea-negative response derived from electrical currents directly generated by photoreceptors. The slower, cornea-positive b-wave has the largest amplitude. Although it is derived from fluxes of potassium ions within and surrounding Müller cells in the inner retina,15 it is directly dependent on functional photoreceptors and its magnitude makes it a convenient measure of the health of photoreceptors.

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• Figure 2. 

  Electroretinograms of a normal individual and patients with forms of stationary night blindness. The tracings in the top row are the responses to single flashes (repeated every 2 seconds, or 0.5 Hz) of blue light that is so dim that only rods are stimulated. The middle row shows the responses to 0.5-Hz, bright, white flashes that stimulate both rods and cones. The bottom row shows the responses to bright, white light flashing 30 times per second (30 Hz); cones but not rods elicit individual responses to light flashing at this frequency. Thus, going from the top to bottom rows, one observes normal rod-isolated responses, combined rod-plus-cone responses, and cone-isolated responses. The time of the light flashes is denoted by the vertical dashed line in the top and middle rows and by the solid vertical lines within the tracings of the bottom row. The letters “a” and “b” in the normal rod-plus-cone electroretinogram (left column, middle row) label the a-wave and b-wave, respectively. The arrows in the tracings of the bottom row denote the cone peak implicit times (that is, the time interval between a light flash and the corresponding peak amplitude). In all tracings, two or three consecutive sweeps are superimposed. The calibration symbol in the lower right corner designates 50 ms horizontally and 100 μV vertically. The column headings refer to the genetic defect causing each patient’s night blindness. Note that the patients with rhodopsin, transducin, and rhodopsin kinase mutations have no observable rod b-waves with these test conditions, whereas the patient with a defective 11-cis RDH (fundus albipunctatus) has a subnormal rod b-wave that becomes normal in amplitude after 5 hours of dark adaptation. Mixed rod-plus-cone responses to 0.5-Hz flashes of bright white light (middle row) are without a prominent cornea-positive b-wave (rhodopsin and rhodopsin kinase cases) or have subnormal b-waves (transducin) except for fundus albipunctatus where the rod-plus-cone b-wave is normal. The rod-plus-cone electroretinograms in fundus albipunctatus would be subnormal after 45 minutes of dark adaptation if the dark-adaptation period had been preceded by exposure to intensely bright light that would bleach a large proportion of the patient’s rhodopsin. In all of these forms of stationary night blindness, cone electroretinograms in response to 30-Hz white flickering light are normal or near-normal in amplitude and have normal peak implicit times (that is, 32 ms or less).

A full-field (Ganzfeld) flash of bright white light will stimulate both rods and cones to give an electroretinogram waveform that sums the contributions of both photoreceptor types. The normal b-wave in response to a flash of bright white light is several hundred microvolts in amplitude, with the exact amplitude depending on the intensity of the flash and other factors. Conditions can be adjusted to measure rod and cone function separately. For example, after dark adaptation for 30 minutes, a flash of sufficiently dim light will stimulate the more light-sensitive rods but not the cones. In this situation, the electroretinogram is termed a “rod electroretinogram” and it will be an indicator of rod function. Cone function can be isolated by stimulating the retina with flashes of bright white light repeated 30 times per second (30 Hz). Rods are too slow to generate responses to individual flashes of light at that frequency. In a normal individual, this 30-Hz, bright, white, flickering light generates a 30-cycle-per-second waveform, called a “cone electroretinogram,” that is derived exclusively from cones and the cones’ indirect stimulation of Müller cells.

All patients with stationary night blindness have severely reduced rod electroretinogram amplitudes, and many have modestly reduced cone electroretinogram amplitudes. Almost all have cone responses with a normal time interval between the light flash and the subsequent peak of the b-wave (that is, normal peak implicit time).16 Among patients with night blindness, a delay in rod or cone electroretinogram peak implicit times even in the face of relatively high amplitudes signifies a progressive retinal degeneration, such as retinitis pigmentosa.16

The absent rod a-wave in the Riggs types of stationary night blindness is used as evidence that the physiologic defects are in the rod photoreceptors themselves,17 whereas the presence of an a-wave but reduced or absent b-wave in the Schubert-Bornschein types point to possible defects in the bipolar cell layer or to the synaptic connection between the rod photoreceptors and the bipolar cells. As described below, these predictions have been substantiated by recent molecular genetic identification of some of the genes causing stationary night blindness.

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The phototransduction cascade 

In response to photons of visible light, a chain of chemical reactions occurs in photoreceptor cells. Scientists have identified many and perhaps most of the proteins involved in this biochemical pathway, called the phototransduction cascade. Rods and cones have similar phototransduction pathways with the protein components being similar but encoded by distinct genes. The chemical reactions that initiate our sense of vision in dim light take place in the outer segments of the rod photoreceptors. Five of the genes so far identified as causes of stationary night blindness normally encode proteins in the rod phototransduction cascade. These proteins are rhodopsin, the α subunit of rod transducin, the β subunit of cGMP-phosphodiesterase, arrestin, and rhodopsin kinase. Their basic roles in the phototransduction cascade are summarized in Figure 3. The normal role of an enzyme in the retinal pigment epithelium (11-cis retinol dehydrogenase), which is defective in fundus albipunctatus, is also indicated in Figure 3. I will now describe the forms of night blindness associated with defects in each of these proteins, and how the defects interfere with the rod phototransduction pathway to cause night blindness. Subsequently, I will describe other forms of night blindness caused by defective proteins not normally involved in the phototransduction cascade.

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• Figure 3. 

  Diagram of the rod phototransduction cascade indicating those proteins defective in forms of stationary night blindness. In the normal pathway, rhodopsin (rho) becomes photoactivated (middle left of figure) and stimulates a number of transducin (Ta) molecules from the inactive, GDP-bound state (Ta-GDP) to the active GTP-bound state (Ta-GTP, four of which are indicated in the figure). Each activated transducin molecule activates in turn a cGMP-phosphodiesterase complex (PDE) formed by an a, b, and two g subunits (only one complex is shown at the top of the figure). Phosphodiesterase hydrolyzes cGMP in the cytoplasm, which will serve to close cGMP-gated cation channels on the cell membrane (not shown), resulting in hyperpolarization of the cell. In the meantime, the photoactivated rhodopsin is ultimately phosphorylated by rhodopsin kinase and then forms a complex with arrestin (top right of figure). The chromophore all-trans retinal separates from rhodopsin, is converted to all-trans retinol, and travels to the retinal pigment epithelium (RPE, denoted by shaded box) to be isomerized back to 11-cis retinol (bottom of figure); 11-cis retinol is converted 11-cis retinal by the enzyme 11-cis retinol dehydrogenase, and the 11-cis retinal travels back to the photoreceptors to combine with opsin that had been dephosphorylated by the action of phosphatase.

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Rhodopsin and dominant stationary night blindness 

The first mutations identified as causes of stationary night blindness were found in the rhodopsin gene.18, 19, 20 In the dark-adapted state, the protein component of rhodopsin, called opsin, is covalently linked to the chromophore 11-cis-retinal, a derivative of vitamin A. A photon of light interacts with the chromophore, changing its conformation to all-trans; this in turn induces conformational changes in rhodopsin that activate it (Figure 3).

Three different dominant mutations in the rhodopsin gene associated with stationary night blindness have been found so far: Gly90Asp, Thr94Ile, and Ala292Glu.18, 19, 20 The mutations are missense changes; that is, they each change a single amino acid residue. Two of the affected amino acids are in the second transmembrane domain of rhodopsin, and one is in the seventh transmembrane domain (Figure 4).

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• Figure 4. 

  Schematic diagram of rhodopsin showing the location of amino acid residues that are altered in cases of stationary night blindness. The protein has an amino terminus in the intradiscal space, seven transmembrane domains, and a carboxy terminus in the cytoplasm. The lysine residue highlighted with a square in the seventh transmembrane domain forms a covalent bond with the chromophore (11-cis retinal, not shown in the figure). The asterisks denote serine and threonine residues near the carboxy terminus that are phosphorylated by rhodopsin kinase. The locations of two asparagine residues (symbol N) near the amino terminus that are glycosylated are shown.

Young patients with one of these mutations report difficulty seeing in dim light, and this poor night vision is reportedly present from the youngest age they can remember. The night blindness is unchanged even after long periods (more than 3 hours) of dark adaptation. The night blindness does not worsen with age. The patients typically have normal visual acuity in both eyes, full visual fields, and normal fundi (Figure 5). Their final dark-adapted thresholds are elevated by approximately 2 to 3 log₁₀ units, meaning that the dimmest light that they can perceive after full dark adaptation is approximately 100 to 1000 times brighter than the dimmest light that normally sighted individuals can see (Figure 1). Light at this intensity can be sensed by the cone mechanism. These patients have a rod mechanism that has a sensitivity decreased by 100-fold to 1000-fold compared with normal. Electroretinograms in these patients have no rod a-wave in response to dim flashes of light, indicating that their physiologic defect involves the rod photoreceptors themselves rather than downstream neurons in the rod mechanism (Figure 2). Cone electroretinogram responses are normal or slightly decreased in amplitude and normal in timing.

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• Figure 5. 

  Photographs of fundi of patients with stationary night blindness. (Left) A 34-year-old patient with night blindness and the rhodopsin mutation Ala292Glu.18 There is no vascular attenuation or other stigmas of retinal degeneration. A choroidal nevus is incidentally present (courtesy EL Berson). (Right) Composite fundus photograph of a 63-year-old affected member of the family with the rhodopsin mutation Gly90Asp (courtesy PA Sieving).19 This patient had night blindness throughout life. Corrected visual acuities are 20/20 in both eyes. There is slight vascular attenuation. Modest atrophy of the retina with some retinal pigmentary deposits are visible in the inferonasal retina. This patient had Goldmann visual fields extending to 115 degrees with the I4e target, with some constriction superiorly corresponding to the fundus pathology, and full-field cone electroretinogram amplitudes at the lower limit of normal (fields and electroretinograms not shown).

Patients with these dominant rhodopsin mutations are heterozygotes with one normal (wild-type) and one mutant copy of the rhodopsin gene. It is reasonable to expect that the rod photoreceptors in these patients have approximately equal amounts of wild-type and mutant rhodopsin. The disease cannot simply be the result of the mutant rhodopsin being inert and nonfunctional, because a 50% reduction in wild-type rhodopsin would correspond to only a 50% reduction in the “quantum catch,” or detection of photons, by rods. But the patients experience over a 99% reduction in sensitivity (over 2 log₁₀ units). Thus, the mutant form of rhodopsin must actively interfere with rod function.

Evidence from in vitro studies of the mutant forms of rhodopsin helps to explain the disease. The mutant rhodopsin molecules have a propensity to stimulate the phototransduction cascade even without exposure to photons of light. It appears that this propensity is related to a physiologic turnover of 11-cis retinal (chromophore) that occurs at a low rate in the dark in normal retinas and presumably also in the retinas of the night-blind patients with one of the rhodopsin mutations.21 Every second in a normal rod photoreceptor in darkness, a few rhodopsin molecules exchange their chromophores.21 Before reattaching to a new molecule of 11-cis retinal, there is a brief interval when the rhodopsin molecule is empty, that is, it is opsin. Unlike normal opsin, the mutant opsins Ala292Glu and Gly90Asp are in an active conformation and stimulate the phototransduction cascade.18, 22 (The Thr94Ile opsin has not been studied in vitro.) In addition, the mutant rhodopsin molecules may have the ability to spontaneously assume an active conformation even while they retain their chromophore, although the rate at which this may occur in vivo is unknown.23

The continuous stimulation of the phototransduction cascade by the changing set of briefly active mutant opsin and rhodopsin molecules physiologically mimics exposure to a constant background light. This desensitizes the rod photoreceptors and explains why the affected patients’ rod photoreceptors can never fully “dark adapt.” In fact, electrophysiologic and psychophysical abnormalities similar to those found in patients with these mutations can be produced in normal patients exposed to a constant background light. The necessary background light intensity corresponds to approximately 10 photoisomerizations per second in each rod photoreceptor,19 which roughly corresponds to the rate of chromophore exchange.21

Although the patients with these rhodopsin mutations are diagnosed as having “stationary” night blindness, some patients over the age of 35 years with the Gly90Asp mutation have a few bone-spicule pigmentary deposits in the periphery of the retina and slight vascular attenuation (Figure 5). Visual fields are full or nearly full in most patients, except for some of those with peripheral retinal pigmentary changes who exhibit a constriction of the visual field.19 Cone electroretinogram amplitudes are low but have normal implicit times.19 The constricted visual fields and decreased cone electroretinogram amplitudes in some patients with the Gly90Asp mutation indicate a modest reduction in peripheral cone function. The reason for mild cone degeneration in patients with defects in rhodopsin, a rod-specific protein, is unknown. It is also not known if this cone degeneration will occur late in life in patients with the rhodopsin mutations Ala292Glu or Thr94Ile. Only one patient with the Ala292Glu mutation has been examined,18 and he had no apparent signs of cone degeneration at his most recent evaluation at age 42 years (EL Berson, personal communication, August 2000). Patients aged 57 and 59 years old with the Thr94Ile mutation had normal fundi and visual fields.20

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The alpha subunit of rod transducin and the nougaret form of stationary night blindness 

Transducin is the protein that mediates the second step in the phototransduction cascade (Figure 3). Photoactivated rhodopsin molecules interact with and activate the α subunit of transducin. There has been only one disease-causing mutation found so far in the gene encoding the α subunit of transducin, and it was found in a single, large family described below. The mutation changes an amino acid in the encoded protein: a glycine at position 38 changes to aspartic acid (Gly38Asp).74

In 1838 Cunier24, 25 described a large family living in southern France with numerous members with night blindness. Church and civil records allowed Cunier to trace the disease to an affected ancestor, named Jean Nougaret, who was a butcher in a small town near Montpellier. Subsequent follow-up reports of this family by Nettleship,12 Truc,13 Dejean and Gassenc,14 and others have documented many hundreds of affected individuals, some of whom are now living in other parts of the world. The Nougaret pedigree was one of the first documented examples of a dominantly inherited human disease.

Individuals affected with Nougaret night blindness have normal fundi (Figure 6) and normal visual fields. There is no worsening of the night blindness with age. The final dark-adapted thresholds are elevated approximately 3 log₁₀ units (Figure 1), and routine electroretinograms show no rod a-wave (Figure 2). Nevertheless, there is evidence from dark-adaptation curves and from specialized electroretinogram techniques that the affected patients have rod photoreceptors that respond to light, although with greatly reduced sensitivity.

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• Figure 6. 

  (Left) Fundus photograph of a 48-year-old man with Nougaret night blindness resulting from the mutation Gly38Asp in the gene encoding rod α-transducin (courtesy E Berson).27 (Right) Fundus photograph of a 14-year-old male with Rambusch night blindness resulting from the mutation His258Asn in the gene encoding the β subunit of rod cGMP-phosphodiesterase (courtesy T Rosenberg).29, 30, 31 The fundi in both the Nougaret and Rambusch forms of stationary night blindness have no vascular attenuation or other signs of retinal degeneration.

In patients with Nougaret night blindness, the cone branch of the dark-adaptation curve shows that the initial rate of cone recovery is normal (Figure 1). However, the cones never achieve normal sensitivity, being approximately 10-fold less sensitive than normal after maximum recovery. A rod-cone break can be observed at about the normal time, suggesting that rods are functional. However, even after prolonged darkness, the rods ultimately become only slightly more sensitive than the cones. The final dark-adaptation threshold is slightly higher than can be sensed by the normal cone mechanism.

In this disease the rod electroretinogram in response to dim light flashes has no a-wave or b-wave. With brighter flashes that would normally stimulate both rods and cones, one can use sophisticated electroretinogram techniques to determine how much of the electroretinogram amplitude is the result of rods versus cones.26 By studying patients with Nougaret night blindness in this way, one finds that their rod photoreceptors are responsive (consistent with the observation of a rod-cone break in the dark-adaptation curve) but that they require light flashes many times more intense than normal to generate a response.27 The reduction in rod sensitivity, the course of dark adaptation, and the electroretinogram findings seen in the Nougaret cases can be simulated in normal individuals by adapting them to a constant background light stimulus.27

The exact mechanism by which the Nougaret mutation in the α subunit of rod transducin causes poorly sensitive rods remains a mystery. Normally, photoactivated rhodopsin induces α transducin to exchange a bound GDP molecule for GTP, a process that activates it (Figure 3). Studies of the mutant transducin in vitro show that it can be activated by rhodopsin and induced to exchange GDP for GTP, but the GTP-bound form of transducin is unable to interact with the next member downstream in the cascade, the γ subunit of rod cGMP-phosphodiesterase.28 However, this cannot be the entire explanation for the observed rod malfunction. Patients with the Nougaret mutation are heterozygotes, and only 50% of their transducin would be nonfunctional, whereas the reduction in their rod function is more than 99%. One speculative explanation that has not been fully explored is that the mutant transducin may compete with wild-type transducin for photoactivated rhodopsin, thereby slowing the rate of activation of the functional wild-type transducin.

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The beta subunit of rod cGMP-phosphodiesterase and the rambusch form of stationary night blindness 

Rod cGMP-phosphodiesterase is the third member of the rod phototransduction cascade (Figure 3). This enzyme is composed of four main subunits: one α subunit, one β subunit, and two γ subunits: During phototransduction in normal retinas, phosphodiesterase is activated by transducin, at which point it rapidly hydrolyzes cGMP in the cytoplasm. The reduction in the concentration of cGMP causes channels on the plasma membrane to close, thereby hyperpolarizing the rod outer segment. This hyperpolarization is transmitted as a neural impulse to the synaptic region of the rod.

A mutation affecting the β subunit of rod phosphodiesterase is a known cause of dominantly inherited stationary night blindness. The only family with this mutation originated in Denmark and was first described in 1909 by a Danish surgeon named Rambusch. The paper was in Danish and did not receive much attention until the family was rediscovered in 1991.29 The Rambusch family is similar to the Nougaret family in size and in the clinical findings of the affected members.29 Night blindness is present from birth, and it does not progress. The fundi are normal (Figure 6). The published dark-adaptation curves and electroretinograms found in this form of night blindness appear indistinguishable from those found in the Nougaret form.

Like the night-blinding mutations in the genes encoding rhodopsin and the α subunit of rod transducin, the defect in the β subunit of rod phosphodiesterase changes a single amino acid. (A histidine normally at position 258 changes to asparagine.)30, 31 Like the rhodopsin and transducin mutants, it is highly unlikely that the night blindness associated with this mutation is merely the result of a 50% reduction in functional phosphodiesterase, because the reduction in rod sensitivity is approximately 1000-fold. There are as yet no reported analyses of the mutant phosphodiesterase enzyme in vitro, so it remains unknown how the mutant protein interferes with the phototransduction cascade to desensitize the rods.

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Rhodopsin kinase, arrestin, and Oguchi disease 

Rhodopsin kinase and arrestin act in sequence to deactivate rhodopsin to stop the phototransduction cascade (Figure 3). Rhodopsin kinase recognizes photoactivated rhodopsin and phosphorylates serine and threonine residues near rhodopsin’s carboxy terminus.32, 33 Arrestin forms a complex with phosphorylated rhodopsin, and this complex prevents further interaction of the activated rhodopsin with transducin. Mutations in either the rhodopsin kinase gene or the arrestin gene cause a recessive form of stationary night blindness called Oguchi disease.34, 35, 36 Unlike the dominant night-blinding mutations in the rhodopsin, transducin, and phosphodiesterase genes discussed above, these recessive mutations are null alleles leading to no gene products or to mutant proteins that are inactive.37

Patients with Oguchi disease have a distinctive dark-adaptation curve (Figure 1). The early cone branch of the curve is normal. Sensitivity plateaus at the cone level for approximately 1 to 2 hours, at which point a rod-cone break occurs and there is a subsequent recovery of full rod sensitivity over the next 1 to 2 hours.36, 38 After this time, affected individuals can see in a dimly lit environment, and their rod electroretinogram in response to a single flash of light will have an a-wave and a b-wave that are normal in amplitude and timing.39 However, there is no electroretinogram response to a second light flash until another prolonged period of dark adaptation has ensued.39

The recovery of light sensitivity in Oguchi disease is related to the time course of rhodopsin regeneration. In a light-adapted retina, many millions of the approximately 40 million40, 41, 42 rhodopsin molecules in each rod have been bleached by photons of light. In a normal retina, these rhodopsin molecules are quickly inactivated through the actions of rhodopsin kinase and arrestin (Figure 3). In a patient with Oguchi disease who lacks either rhodopsin kinase or arrestin, photoactivated rhodopsin molecules continue to activate transducin, thereby desensitizing the rods. Each photoactivated rhodopsin molecule will stay active until its photoisomerized chromophore, all-trans retinal, is lost. The time course of replacing rhodopsin’s all-trans retinal with 11-cis retinal, a process referred to as regeneration of rhodopsin, occurs according to an exponential function with a half-life of approximately 4 to 7 minutes in normal retinas and in retinas with Oguchi disease.38, 43, 44, 45 The rate of this process will require more than 2 hours to regenerate a few million bleached rhodopsin molecules with fresh 11-cis retinal. Patients with Oguchi disease must wait for complete regeneration of almost all of their rhodopsin molecules before the rods will regain full sensitivity. This is because even a handful of remaining, active rhodopsin molecules in a rod are sufficient to continuously stimulate the phototransduction cascade, thereby desensitizing the rod photoreceptor just as a background light would.

Rhodopsin kinase is present in cone photoreceptors as well as rod photoreceptors, and it appears to phosphorylate activated cone opsin. One would expect that patients with Oguchi disease resulting from a nonfunctional rhodopsin kinase should have a defect in cone function. In fact, a subtle abnormality in the recovery of cone function after a bleaching light was detected in one such patient.36 A more severe, subjectively discernible abnormality of cone function did not occur, possibly because cones may rapidly replace isomerized chromophore. This would decrease the need for deactivation of cone opsin before its regeneration with fresh 11-cis retinal.

There is one other distinctive feature of Oguchi disease. While the color of the fundus is normal after prolonged dark adaptation, it changes to a dark or golden hue after a few minutes in the light (Figure 7). The color change is called the Mizuo phenomenon or the Mizuo-Nakamura phenomenon,46 and its biochemical basis is not known. Some authors speculate that it is the result of elevated extracellular potassium levels generated in the retina in response to an excessive stimulation of rod photoreceptors.47

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• Figure 7. 

  Fundus photographs of patients with Oguchi disease. (Top left) A patient homozygous for the arrestin mutation Asn309(1-bp del) (also known as 1147delA) after 12 hours of dark adaptation. (Top right) After 30 minutes of light adaptation, the same region of the retina has a golden color (the Mizuo-Nakamura phenomenon). (Bottom left) Fundus photograph of a 55-year-old woman with Oguchi disease (from Nakazawa and associates, Retina69 reprinted with permission). (Bottom right) Fundus photograph of her 58-year-old brother with retinitis pigmentosa. Both siblings were homozygous for the arrestin mutation Asn309(1-bp del), a reported cause of Oguchi disease.50, 69 (Photographs courtesy M Nakazawa.)

Patients reported in the literature with mutations in the rhodopsin kinase gene have Oguchi disease with no signs of photoreceptor degeneration.35, 36, 37 However, some patients with mutations in the arrestin gene have some features of Oguchi disease, such as the Mizuo-Nakamura phenomenon, and also have photoreceptor degeneration similar to retinitis pigmentosa.48, 49, 50 In at least one family, two affected siblings homozygous for the same arrestin gene defect differed in their phenotypes: one had classic Oguchi disease, the other retinitis pigmentosa (Figure 7).50 It remains a mystery why retinitis pigmentosa develops in some patients. Little insight into this question has come from animal models: elimination of the function of arrestin in fruit flies uniformly causes a photoreceptor degeneration that is dependent on exposure to light.51 Also, transgenic mice homozygous for an arrestin mutation have been created.52 My fundus examination of these mice revealed no apparent sign of retinal degeneration nor was there an apparent change in fundus color with light adaptation (unpublished observation).

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11-cis retinol dehydrogenase (11-cis rdh) and fundus albipunctatus 

The five proteins discussed above are all found in rod photoreceptors and participate in the rod phototransduction cascade; 11-cis RDH is found instead in the retinal pigment epithelium. It is a key enzyme necessary for the production of 11-cis retinal, which is then transported to the neighboring photoreceptors for use as the chromophore in rhodopsin and in the cone opsins (Figure 3). Mutations in the gene encoding 11-cis RDH cause a distinct form of stationary night blindness called fundus albipunctatus.53, 54, 55, 56, 57

Patients with fundus albipunctatus complain of night blindness or of delays in dark adaptation after exposure to bright light. Their fundi have numerous small, white or pale-yellow dots scattered in the retina, which may or may not involve the macula (Figure 8). In cases followed over 13 to 14 years (from ages 33 to 47 years and from 8 to 21 years), some of the dots did not change, some became more prominent, a few new dots appeared, and still others faded.58 All of the dots can fade in patients during the fourth to fifth decade.55 Similar dots and the symptom of night blindness occur in patients with dietary vitamin A deficiency and in patients with vitamin A deficiency resulting from a lack of β lipoprotein (Bassen-Kornzweig syndrome)4 or a lack of serum retinoid-binding protein,59 and these treatable diseases should be considered in the differential diagnosis.

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• Figure 8. 

  (Left) Fundus photograph of fundus albipunctatus in a 49-year-old woman who is homozygous for the missense mutation Gly238Trp in the gene encoding 11-cis RDH (from Yamamoto and associates, Nature Genetics53 reprinted with permission). Numerous subretinal dots are present, including some in the macula. (Right) Fundus photograph of a 49-year-old man with fundus albipunctatus resulting from a mutation in 11-cis RDH and a “bull’s-eye” maculopathy and numerous dots elsewhere in the retina (courtesy Y Miyake). The electroretinograms of this patient are shown in Figure 9.

The dark-adaptation curve in fundus albipunctatus features a prolonged recovery of cone sensitivity as well as a prolonged recovery of rod sensitivity (Figure 1). Electroretinogram rod and cone amplitudes are substantially reduced after a standard 30 to 40 minutes of dark adaptation, but they may come to normal or near-normal levels after many hours of dark adaptation (Figure 2). These defects are understandable in view of the mutations leading to a deficiency of 11-cis RDH.53, 54, 55, 56, 57 Without this enzyme, the production of 11-cis retinal in the retinal pigment epithelium is compromised, and the deficient supply of chromophore to the photoreceptors delays the rate at which they can recover after bleaching. The fact that the photoreceptors ultimately do recover suggests that the mutant forms of the enzyme have a residual activity or that alternative enzymes or biochemical pathways may supply 11-cis retinal at a slower-than-normal rate. In fact, careful measurement of the dark-adaptation curve in fundus albipunctatus shows a biphasic recovery of light sensitivity, which was interpreted as evidence for more than one pathway that generates chromophore.56

Fundus albipunctatus has been categorized as a nonprogressive form of night blindness. However, some cases in their thirties, forties, or older have symptoms and signs of cone degeneration, including reduced visual acuity, a macula with a bull’s eye appearance (Figure 8) or an atrophic patch, and a reduction in cone electroretinogram amplitudes and delays in cone electroretinogram implicit times even after many hours of dark adaptation (Figure 9).57, 60 Such cases have defects in the 11-cis RDH gene similar or identical to those found in typical fundus albipunctatus. It remains unclear whether cone degeneration is present to a greater or lesser degree in all patients with fundus albipunctatus, or whether it is found only in a subset of patients who perhaps have as yet obscure environmental exposures or modifying genes. Because the apparent physiologic problem in fundus albipunctatus is the supply of 11-cis retinal to photoreceptors, it is possible that measures that reduce the photoreceptors’ need for 11-cis retinal (for example, the wearing of dark sunglasses) might prevent or delay cone degeneration.

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A retinal L-type calcium channel and the incomplete form of X-linked stationary night blindness 

Two forms of X-linked stationary night blindness exist that were originally distinguished by differences in electroretinograms.10 The electroretinograms of both forms have intact rod a-waves and diminished rod b-waves, and thus both are of the Schubert-Bornschein type. However, in one, called the incomplete type, a subnormal rod b-wave is clearly evident, whereas in the other, called the complete type, the rod b-wave is absent under all test conditions.10 The X-linked incomplete and complete forms are caused by distinct loci on Xp, and neither is allelic with known X-linked retinitis pigmentosa loci.61

Central visual acuity is typically decreased in both forms of X-linked stationary night blindness. The average patient has an acuity of approximately 20/50, but it can be reduced to counting fingers in some patients.10, 62 The incomplete form of X-linked stationary night blindness is not associated with high myopia (the average refractive error is −0.8 spherical equivalent).10 In contrast, patients with the complete form typically are myopes, with the average refractive error being about −8 diopters.10 The fundi may be normal even in those patients with subnormal visual acuity (Figure 10). In those patients with severely reduced acuity, there is typically a corresponding chorioretinal atrophy in the macula. Nystagmus and strabismus can be a feature of both forms.10 The dark-adaptation curve of the incomplete type shows a modest reduction in the rate of cone recovery, an intact rod-cone break, and a reduction in the rate of rod recovery with final dark-adapted thresholds approximately 1.0 to 1.5 log₁₀ units above normal (Figure 1).10 In the complete form, the dark-adaptation curve shows only a cone component, and the rate of cone recovery of light sensitivity is slower than normal in most cases (Figure 1).10

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• Figure 9. 

  Full-field electroretinograms of the 49-year-old man with fundus albipunctatus and cone degeneration. These electroretinograms were recorded with techniques somewhat different from those described in the legend of Figure 2.10 The photoreceptor mechanism evaluated is labeled at the left of each row and corresponds to that in Figure 2. The rod (scotopic) signal (top row) achieves a normal amplitude within 3 hours of dark adaptation, whereas the cone electroretinograms to 30-Hz flickering light (bottom row) have an abnormally reduced amplitude. Calibration symbols for each row are at the lower right corner of the normal electroretinogram waveforms in the left column (courtesy Y Miyake).

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• Figure 10. 

  Fundus photographs of (left) a 19-year-old man with X-linked incomplete stationary night blindness and visual acuity of 20/30, and (right) an 18-year-old man with X-linked complete stationary night blindness and visual acuity of 20/50 (courtesy Y Miyake). Despite the subnormal visual acuities, the maculas appear normal. The electroretinograms of these patients are shown in Figure 11.

In dark-adapted patients with the incomplete type of stationary night blindness, a subnormal rod b-wave is clearly discernable (Figure 11). The cone electroretinogram amplitude in response to 30-Hz flickering light is reduced (Figure 11). The cone electroretinogram amplitude increases substantially (over 300% in some cases) during light adaptation (for example, after 12 to 15 minutes of continuous 30-Hz flickering light).63 The increase in the cone electroretinogram with light adaptation is much larger than what is observed in normal individuals (100% to 220%) or in patients with complete stationary night blindness, with other forms of stationary night blindness, or with retinitis pigmentosa.63 Nevertheless, the final cone electroretinogram amplitude is still below normal in patients with incomplete stationary night blindness. In the complete type of X-linked stationary night blindness, there is no discernable rod b-wave and the cone electroretinogram amplitudes are normal or near normal and the cone peak implicit time is also normal (Figure 11).10, 62 A study of visual evoked potentials suggests that in the incomplete form there is an abnormal excess of ganglion cell axons crossing at the chiasm, similar to what is seen in albinism.64 It is not known whether this abnormality is also present in the complete form.

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• Figure 11. 

  Electroretinograms of (left) a normal individual, (middle) a 19-year-old man with X-linked incomplete stationary night blindness, and (right) an 18-year-old man with X-linked complete stationary night blindness (SNB). The rod-plus-cone electroretinograms in the middle row shown here were elicited in response to light flashes considerably more intense than used for the electroretinograms in Figure 2. These intense light flashes normally produce a larger a-wave which is mostly due to the rod photoreceptors. The patient with incomplete night blindness has an intact rod a-wave (seen in the middle row) and a reduced rod b-wave (seen in the top row) that is slightly delayed in timing. This patient also has a markedly reduced cone amplitude in response to 30-Hz light pulses (bottom row). The patient with complete night blindness has an intact rod a-wave (middle row), no rod b-wave (top row), and normal cone amplitude (bottom row) (courtesy Y Miyake).

Based on the intact rod electroretinogram a-wave, the pathologic defects in both forms of X-linked stationary night blindness are thought not to directly involve the rod phototransduction pathway. Because of the abnormal rates of dark adaptation of both rods and cones, these forms of night blindness may affect both the rod and cone mechanisms. The defects are likely to be in the synaptic transmission of neural signals from photoreceptor cells to higher-order neurons or to defects in the higher-order neurons themselves.

Whereas the gene for the complete type of X-linked stationary night blindness remains unknown, the gene for the incomplete type of X-linked stationary night blindness has been identified.65, 66 It codes for the pore-forming subunit of an L-type voltage-gated calcium channel that is found mainly in the retina. It is not yet known whether this channel is one of the voltage-gated calcium channels that modulates the release of the neurotransmitter glutamate from photoreceptor cells, or if it has a role in the depolarization of bipolar or horizontal cells in response to light-stimulated rod photoreceptors. Analysis of electroretinogram waveforms in response to light flashes lasting 125 ms suggests that the defect involves cone synapses rather than inner retinal neurons.67 The explanation for the decreased acuity, as well as the likely secondary nystagmus and abnormal decussation of ganglion cell axons, probably awaits a better understanding of the function of the L-type calcium channel.

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Conclusion 

The identification of genes causing some forms of stationary night blindness in the last 8 years has greatly increased our understanding of this group of diseases. We have learned that rod photoreceptors are alive and functioning, although abnormally, in the forms of night blindness with identified gene defects. In some types of the disease, such as fundus albipunctatus, cones are abnormally functioning as well. Finally, some forms of “stationary” night blindness are associated with reduced central visual acuity and/or a progressive decrease of cone function. Examples are the rhodopsin mutant Gly90Asp and some arrestin mutations causing signs of retinitis pigmentosa, and mutations in 11-cis RDH causing cone degeneration. It is probably still appropriate to retain the term stationary night blindness for some of these mutants.

One should remember that photoreceptor function decreases in everyone with age. For example, maximum electroretinogram b-wave amplitudes for normal individuals in their sixties are about half of what they are in 15 to 24 year olds.68 In some patients with the rhodopsin mutation Gly90Asp, the apparent decrease in cone function is closer to 80% in this age interval.19 From a patient’s point of view, the question becomes whether the rate of decline in photoreceptor function is sufficient to cause substantial visual loss during a normal life span. If not, then it is probably better to specify a diagnosis of “stationary” night blindness with a greater-than-normal rate of decrease in visual function rather than a diagnosis of retinitis pigmentosa (“progressive” night blindness) that is so mild that no incapacitating visual loss is anticipated during the patient’s life. However, for the Oguchi-type mutations causing retinitis pigmentosa, the 11-cis RDH mutations causing fundus albipunctatus with cone degeneration, or for patients with incomplete or complete X-linked stationary night blindness and subnormal visual acuity, the nomenclature is not so clear cut. Some older patients with fundus albipunctatus or with X-linked stationary night blindness ultimately become legally blind. It is worthwhile to search for agents that might help reduce the visual decrease associated with these forms of night blindness. With the atrophic maculas in these patients, it is likely that, without the pre-existing diagnosis of night blindness, they would be diagnosed with age-related macular degeneration. An electroretinogram would help to make the correct diagnosis, which could be confirmed through molecular genetic analysis.

There are undoubtedly additional forms of stationary night blindness resulting from novel genes that will be discovered over the next few years. Studies of affected patients, of transgenic mouse models, and of mutant proteins will rapidly augment our understanding of the pathophysiology of these diseases. This review of these diseases will soon become outdated and incomplete, if it is not already by the time it is published. Still, just as Dunphy’s 1963 Jackson Lecture on retinoblastoma helped my early career, I hope that this article will serve as a foundation of basic knowledge for ophthalmologists and scientists who are trying to fully understand stationary night blindness and how it differs from normal vision and from degenerative retinal diseases such as retinitis pigmentosa.

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Acknowledgements 

I thank Drs Eliot L. Berson, Michael A. Sandberg, Yozo Miyake, Mitsuru Nakazawa, Thomas Rosenberg, and Paul A. Sieving for providing fundus photos, electroretinograms, and other clinical data on their patients, and Terri McGee and Kevin McDermott for expert construction of the figures.

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