possible that functioning blue cones in the parafoveal region account for the slightly improved acuity. Some have suggested that the improved acuity results not from residual blue cone function but from retention of a lesser degree of additional residual red and green cone function,571 because some blue cone monochromats have residual sensitivity to longer wavelengths,508 as evidenced clinically by their ability to correctly identify some red–green color plates. The observed genetic heterogeneity in blue cone monochromatism could account for this observation.418

Recent advances in functional brain imaging have allowed insights into the large-scale reorganization of the visual pathway that occurs in rod monochromatism. A large-scale developmental reorganization of the visual pathway was shown in rod monochromats who lack cone photoreceptor function. In rod monochromats, the cortical region that normally responds to cones during functional MR imaging activation responded powerfully to rod-initiated signals.51,232

Leber Congenital Amaurosis

Leber congenital amaurosis is usually an autosomal ­recessive retinal dystrophy characterized by congenital blindness, nystagmus, sluggish pupillary responses to light, and minimal retinal abnormalities in infancy. As detailed in Chap. 1, numerous different genes have been identified that cause Leber congenital amaurosis.536 Some mutations produce cone-rod dystrophies while others produce rod-cone dystrophies.

Affected patients may manifest roving eye movements or a large-amplitude, low-frequency nystagmus (in keeping with the low visual acuity).307 Less commonly, the nystagmus may be upbeating, in which case it may be asymmetrical.222 Pupillary responses are absent or sluggish. These infants characteristically demonstrate the “oculodigital” sign in which the thumbs or fists are habitually used to apply pressure to the closed eyes. Facial features of Leber congenital amaurosis may include enophthalmos (possibly from chronic eye rubbing) and maxillary hypoplasia. Unlike other congenital retinal dystrophies characterized by myopia, high hyperopia is seen in about half of patients with Leber congenital amaurosis. The diagnosis is established by a nonrecordable or highly attenuated ERG. Over time, retinal pigmentary abnormalities become evident and the optic discs become pale. Acquired retinal pigmentary abnormalities can range from a fine pigment granularity to diffuse marbleization of the fundus. Occasionally, infants with Leber congenital amaurosis have bilateral staphylomatous macular lesions. Despite the fact that retinal pigmentary changes are acquired, most patients do not experience progressive visual loss.272

Early studies noted a high incidence of mental retardation and neurological problems in Leber congenital amaurosis. It is likely that these studies included patients with a variety

of primary neurometabolic and neurodegenerative diseases that would be more readily detected with modern diagnostic techniques. Although the great majority of children with Leber congenital amaurosis appear to be intellectually and neurologically normal, mental retardation, developmental delay, hearing loss, epilepsy, hypotonia, and cerebellar abnormalities are seen in a small subset of patients. Leber congenital amaurosis is usually an autosomal recessive condition that is genetically heterogenous. As discussed in chapter 1, numerous causative mutations have now been identified,

Alström Syndrome

The association of tachypnea with nystagmus is well recognized in Joubert syndrome, but can also be a presenting sign of Alström syndrome.130,391,475 Alström syndrome is an autosomal recessive disorder characterized by obesity, sensorineural deafness, and cone-rod dystrophy, all appearing during the first decade of life. Infants can manifest respiratory distress, tachycardia, and hepatomegaly secondary to a dilated cardiomyopathy with left ventricular dilation and decreased myocardial function. Infants that survive the initial episode often show progressive improvement, with little evidence of a long-term deleterious effect in cardiac function.

The onset of the cardiomyopathy in infancy suggests that the heart defect may be expressed only during a specific developmental stage and that the minimal but persistent dilation observed on followup is a sequel to the decompensation in infancy, rather than the result of an active process.391 An evaluation of 182 Alström patients by Marshall and colleagues380 led to the identification of additional phenotyping features, including urological, gastrointestinal, pulmonary, and neurobehavioral abnormalities. Although there is overlap with Bardet-Biedl syndrome, there is no polydactyly, mental retardation, or hypogonadism in Alström syndrome.535 The ALMS gene is mutated in Alström syndrome. This gene is ubiquitously expressed, and the encoded protein localizes to centrosomes and ciliary basal bodies.112 However, mutant alleles are associated with age-dependent loss of primary cilia, suggesting that the Alström syndrome phenotype results in impaired cilia function rather than abnormal cilia development.112,174

Rod-Cone Dystrophies

Congenital Stationary Night Blindness

Congenital Stationary Night Blindness (CSNB) is characterized by night blindness, nystagmus, decreased visual acuity, and a normal retinal examination. Visual acuity can range

from 20/20 to 20/200. High myopia is common and affected children frequently have paradoxical pupillary responses to light. Pieh et al447 analyzed the ­nystagmus in 10 patients with CSNB and found a continuous pendular, oblique and mostly dysconjugate nystagmus of high frequency and low amplitude in all patients. In seven patients, a large, mostly intermittent and conjugate horizontal or vertical jerk nystagmus was superimposed. The nystagmus of CSNB was similar to the nystagmus reported in blue cone monochromatism and rod monochromatism.447 Profound fear in darkness can be the presenting symptom.184a Tonic downgaze with a chin-up head posture can be another presenting feature of CSNB.504a

CSNB can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion, with X-linked inheritance being the most common pattern.447 Decreased visual acuity, myopia, and nystagmus are seen in X-linked CSNB and in some patients with autosomal recessive CSNB, but not in autosomal dominant CSNB.288,447 In X-linked CSNB, visual acuity generally ranges from 20/30 to 20/100.421 Congenitally tilted discs and optic disc pallor have been noted in some patients with X-linked CSNB.270,287a

The diagnosis of CSNB is established by ERG. Most patients with the X-linked and autosomal recessive forms of CSNB have a near-normal a wave and a substantially reduced b wave (referred to as an electronegative ERG) when tested under dark-adapted bright-flash conditions (Schubert– Bornschein type).404,405,474 When the intensity of the test stimulus is increased, the amplitude of the a wave increases while that of the b wave remains unchanged. The photopic b wave may also be reduced together with a characteristic loss of the early components of the oscillatory potentials, leading to a “squared-off” appearance to the photopic ERG a wave.270,575 In pedigrees with autosomal dominant CSNB, the scotopic waveform is electropositive; and there is a reduced but normal photopic response that does not decrease in amplitude under scotopic conditions210 although rare electronegative waveform have been reported267,134,430

CSNB is caused by mutations arising in genes that encode components of the phototransduction cascade or proteins that may be involved in signaling from photoreceptors to adjacent second-order neurons.447 CSNB1 (the complete type) results from mutations in the NYX gene (nyctalopin gene) that is located on the X chromosome.211 These mutations lead to a complete defect of the ON-bipolar cells or their synapses in the rod and cone visual pathways, leaving the OFF pathway intact.54,55 X-linked recessive CSNB2 (the incomplete type) arises from mutations in the calcium channel (CACNA1F) gene, which encodes the retina-specific alpha 1-subunit. Alterations induce severe changes in channel activity, leading to an incomplete defect of the ON and OFF bipolar cells or their synapses in the rod and cone visual pathways.289 Mutations in CABP4, a member of the calciumbinding protein family have also recently been found to lead

to CSNB2.603 CSNB1 and CSNB2 both show a negative ERG with a decreased b-wave in the scotopic as well as the photopic ERG.410 Rod function is most severely affected in CSNB1 and less impaired in CSNB2.72 The oscillatory potentials of the multifocal photopic ERG show reduction of only the first peak amplitude in CSNB1, whereas in CSNB2, both peak amplitudes are barely discernible from noise, suggesting­ possible involvement of a postreceptor pathway of cone signal processing.447,486

No histologic abnormality of the retina in CSNB has been identified, and rhodopsin concentration and regeneration, as determined by retinal densitometry, are also normal.470,575 An acquired form of night blindness with electronegative ERGs that are similar but not identical to those in CSNB can be seen as a paraneoplastic effect in patients with cutaneous malignant melanoma. Immunohistochemistry has demonstrated heavy immunostaining of rod bipolar cells in patients with this condition.394 The combination of ocular hypopigmentation and an electronegative ERG may be seen in Forsius–Erickson syndrome (Åland eye disease). Åland eye disease is an X-linked disorder characterized by subnormal visual acuity, myopia, astigmatism, dyschromatopsia, night blindness, nystagmus, hypopigmentation of the iris, and chorioretinal hypopigmentation, foveal hypoplasia, normal skin melanosomes, and an electronegative ERG.449 Alitalo et al22 have localized Åland eye disease to the pericentromeric region of the X chromosome.22,216 Although this condition has been considered a form of ocular albinism, its nosology is open to question because affected patients do not have the hemispheric VEP asymmetry seen in ocular albinism.544 Weleber et al have suggested that Åland eye disease and the incomplete form of CSNB may be the same disease.575 Linkage data from patients with incomplete CSNB support this hypothesis.412 VEP evidence of interhemispheric asymmetry with contralateral dominance (indicating misrouting of optic nerve fibers) has been found in approximately 15% of patients with CSNB.543

About 80% of patients with Duchenne muscular dystrophy have electronegative ERGs that are similar to but distinguishable from those seen in CSNB.105 Most affected patients have point mutations in the dystrophin gene. Unlike in CNSB, patients with muscular dystrophy are not myopic, photophobic, or nyctalopic, either clinically or by dark adaptation studies.132 Visual acuity is generally unaffected, although many patients have increased macular pigmentation.501 Fitzgerald et al197 were the first to localize the abnormal retinal signal transmission in Duchenne muscular dystrophy to the photoreceptor/ depolarizing bipolar cell synapse. Pillers et al have identified an additional subgroup of patients with muscular dystrophy, glycerol kinase deficiency, and adrenal hypoplasia that appears to be attributable to a contiguous gene syndrome that includes the muscular dystrophy gene. They have termed this disorder “Oregon eye disease” and tentatively mapped the deletion to Xp21.449