Chapter 111 – Congenital Stationary Night Blindness
KENNETH G. NOBLE
• Nonprogressive poor night vision present since birth.
• Normal fundus (inherited as autosomal dominant, autosomal recessive, or X-linked recessive).
• Abnormal fundus (Oguchi’s disease, fundus albipunctatus).
• The pathology has an anatomical locus, as revealed by visual function tests.
• Molecular genetic studies suggest pathogenetic mechanisms in certain types.
Nowhere in ophthalmology does the name of a disorder so aptly and completely describe all the essentials of the disease as congenital stationary night blindness (CSNB). The early onset of nonprogressive night vision difficulty is the hallmark of CSNB. However, CSNB is not a single disease but rather encompasses diverse disorders that share this common feature. None of the variants is currently treatable. The disorders of CSNB are divided conveniently into two groups: those with a fundus of normal appearance and those with an abnormal fundus.
A fundus of normal appearance with CSNB is inherited as autosomal dominant, autosomal recessive, or X-linked recessive. Because the clinical appearance of these eyes is normal, diagnosis is based on history and ancillary testing.
The paradigm for autosomal dominant inheritance is exemplified by the complete genealogical records of two large pedigrees with CSNB, which began in the seventeenth century and span 11 generations—the Nougaret family of France  and the Danish family studied by Rambusch. Patients who have autosomal dominant CSNB almost invariably have normal vision without a significant refractive error. This is in contradistinction to a significant number of patients in whom CSNB is inherited in the recessive mode (autosomal and X-linked), and who seek treatment for night blindness in association with poor vision, nystagmus, and high-grade myopia. When present, these features can muddle the diagnosis of CSNB.
Specific psychophysical and electrophysiological studies are useful for understanding these diseases and confirming the diagnosis. The initial distinction was based on two different electroretinographic (ERG) findings, named after the investigators who first described them. In 1952, Schubert and Bornschein described a progressive increase in the initial negative response (a wave) during dark adaptation, but without a corresponding increase in the subsequent positive response (b wave). This electronegative ERG finding in CSNB is known as the Schubert–Bornschein response and is seen mostly in autosomal recessive and X-linked recessive CSNB. In 1954, Riggs published the finding of a reduction in amplitude but normal waveform of the photopic response which, under scotopic conditions, manifested only a slight increase in amplitude. The Riggs ERG finding is seen mostly in autosomal dominant CSNB, including members of both the Nougaret and Rambusch families. However, either ERG response may occur in families with the various inheritance patterns.
In the initial studies, rhodopsin pigment concentrations and kinetics measured by fundus reflectometry were found to be normal in patients with CSNB who had a fundus of normal appearance. This finding places the site of pathology proximal to the rod outer segments. In the Schubert–Bornschein response, with a deep a wave of normal appearance, the abnormality is hypothesized to be in the midretinal layer. The abnormal a wave seen in the Riggs response suggests the inner segments of the photoreceptors as the primary site. However, a subsequent study of fundus reflectometry identified a group of patients with CSNB who had abnormal rhodopsin kinetics.
Another classification, complete and incomplete CSNB, is suggested on the basis of visual function studies performed on patients with autosomal recessive and X-linked recessive CSNB who manifested the Schubert–Bornschein electronegative ERG findings. The complete type of CSNB manifests no detectable rod function, with only a slight reduction in cone function in association with diminished vision and myopia. The incomplete type of disease manifests some remaining rod function, more severe cone dysfunction, visual acuity loss, and no specific refractive error. There are now reports confirming a genetic basis for the distinction, because participating family members were found to have either the complete or incomplete type of CSNB.
The incomplete type of X-linked CSNB is associated with a gene that affects the L-type voltage-gated calcium channels. The pathogenetic mechanism is not clear, but it may affect photoreceptor cell neurotransmission or midretinal neural receptors and their responses. The complete type of X-linked CSNB is found at a different locus on the X chromosome.
Studies of molecular genetics have been informative, as well, for dominant CSNB. The possibility that CSNB and retinitis pigmentosa may be allelic suggested candidate genes for study. A heterozygous missense mutation in the rhodopsin gene (Ala292Glu) was confirmed in one patient with CSNB in whom the mode of inheritance could not be determined. Subsequently, studies in families who have dominant inheritance revealed two additional missense mutations in the rhodopsin gene (Gly90Asp) (Thr94Ile). 
Linkage analysis in a large Danish family (Rambusch pedigree) showing autosomal dominant inheritance of CSNB assigned the locus to the distal chromosome 4p near the gene that encodes the subunit of rod photoreceptor cGMP-phosphodiesterase (ßPDE). Because a homozygous nonsense mutation in ß-phosphodiesterase had been described recently in autosomal recessive retinitis pigmentosa, this gene was sequenced in the Rambusch pedigree and
a heterozygous missense mutation (His258Asp) was identified in affected family members.  In the Nougaret family a missense mutation resulting in one amino acid substitution (Gly38Asp) in the a subunit of transducin has been identified. In summary, three different proteins (rhodopsin, the subunit of rod cGMP-phosphodiesterase, and the a subunit of rod transducin), each with one missense mutation and one amino acid substitution, result in autosomal dominant CSNB. Each of these proteins participates in the phototransduction cascade.
A hypothetical pathogenetic model called constitutive activation has been proposed to account for the clinical findings. With abnormalities in a protein that participates in phototransduction, there is a continuous ever-present low level of illumination even in the absence of light or the chromophore. This does not allow for full dark adaptation of the rods, which are constantly desensitized, especially in low illumination. This pathophysiological process may be a common final pathway when the phototransduction cascade is affected (see Oguchi’s disease ).
Histopathology studies of these disorders are quite rare. Two well-documented cases, of the Riggs and Schubert–Bornschein types, respectively, agreed that the rod and cone photoreceptors are histopathologically normal. A recent study (Schubert–Bornschein type) remarked on disorganization of the outer plexiform, outer nuclear, and inner nuclear layers.
A fundus of abnormal appearance in association with CSNB includes Oguchi’s disease and fundus albipunctatus. These two diseases have very little in common, save early-onset nonprogressive night blindness.
A series of articles in the early twentieth century by the Japanese ophthalmologist C. Oguchi stamped his name on this most unusual disease. The characteristic yellowish metallic sheen of the posterior pole places the retinal vessels in stark relief and serves to establish the diagnosis on a clinical basis ( Fig. 111-1 , A). After prolonged dark adaptation the yellowish fundus appearance reverts to normal, a phenomenon described by and named after Oguchi’s countryman, Mizuo ( Fig. 111-1 , B). Reexposure to light results in the return of the metallic sheen.
The abnormal fundus color and the reversion to normal after dark adaptation suggest an abnormality in the rod photopigment, rhodopsin. However, the delay in dark adaptation (normal rod thresholds reached only after several hours) does not correlate with the Mizuo phenomenon. In addition, fundus reflectometry studies document both normal rhodopsin concentrations and normal regeneration kinetics.
Cone function seems normal because cone adaptation, final cone thresholds, and the photopic ERG response are normal. Rod function is abnormal, with normal rod thresholds reached only after 4 hours or longer (normal is 30 minutes) and scotopic ERG showing only a small electronegative response, even when the rod thresholds have reached normal.
Rhodopsin kinase and arrestin are both responsible for terminating the phototransduction cascade. A null allele in the genes for each of these proteins is responsible for Oguchi’s disease.  Therefore, in a similar fashion as discussed with other forms of CSNB, the persistent low level of light may desensitize the rods continually.
There are several conflicting histopathological reports, which include the identification of a pigmented cellular layer interposed
Figure 111-1 Oguchi’s disease. A, The yellowish metallic sheen is apparent nasal to the optic disc. B, After 3 hours of dark adaptation the fundus reverts to the normal coloration (Mizuo phenomenon).
between the normal retinal pigment epithelium and photoreceptors, an abnormal layering of lipofuscin between the retinal pigment epithelium and photoreceptors,  and abnormal numbers, arrangement, and structure of the cones.
Like Oguchi’s disease, fundus albipunctatus has a distinctive fundus appearance which should immediately suggest the diagnosis. There are multiple tiny white dots that are monotonous in their
Figure 111-2 Fundus albipunctatus. The posterior pole and beyond shows multiple small, discrete, round, white dots which spare the fovea.
perfect regularity. They involve the posterior pole, spare the macula, and extend into the midperiphery ( Fig. 111-2 ). Fluorescein angiography shows focal areas of transmission hyperfluorescence, which do not correlate with the fundus pathology.
Visual pigments of both rods and cones show a delay in regeneration that correlates with the delay in visual function studies. During dark adaptation the return to normal of both the rods and cones is prolonged, and there is a delay in the cone–rod break. The reduced amplitudes of the ERG a wave and b wave of the photopic and scotopic responses are diminished under normal test conditions, but the scotopic response slowly returns to normal after a few hours in the dark. The prolonged delay in dark adaptation is due to a mutation in the gene for 11-cis retinol dehydrogenase. This enzyme converts 11-cis retinol to 11-cis retinal in the retinal pigment epithelium, and it then is transported to the photoreceptor to combine with opsin as rhodopsin. The delays in both adaptation and the ERG are consistent with a mutation in this enzyme.
The term congenital stationary night blindness comprises a heterogeneous group of disorders that have a common history but differ considerably in terms of clinical pictures and visual function studies. An awareness of the distinguishing findings should suggest the correct diagnosis. For a more thorough discussion of this subject the reader is referred to the LVII Edward Jackson Memorial lecture by Thaddeus P. Dryja, MD, entitled Molecular Genetics of Oguchi Disease, Fundus Albipunctatus, and Other Forms of Stationary Night Blindness. 
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