Congenital Retinal Dystrophies

over normals to match central hues with surrounding shades of gray on the basis of brightness.421,433 The retinal appearance remains normal in most cases and cone-like structures have been identified histologically in the photoreceptor layer.190,264 OCT usually shows a normal thickness of the foveal nerve fiber layer, but some cases have missing outer segments in the center of the retina.

Achromatopsia is recessively inherited and genetically heterogeneous. The three genes associated with achromatopsia (CNGA3, CNGB3, and GNAT2) encode proteins in the cone phototransduction cascade.338,339 CNGA3, on region 2q11, encodes the a subunit of the cGMP gated (CNG) cation channel in human cone photoreceptors, the final critical effector in the phototransduction cascade. CNGB3, on region 8q21-q22, encodes for the b subunit of cone photoreceptor CNG cation channels. GNAT, on region 1p13, codes for the a subunit of cone specific transducin. CNGA3 and CNGB3 mutations seem to be responsible for most cases.585, 531a Some cases of incomplete achromatopsia can have residual function of C, M, or S cones. There are no discernable phenotypic differences between the genotypes.173,547 The finding of rough brown teeth in the child with apparent achromatopsia is a signature of amelogenesis imperfecta.182,305,393

Glasses or contact lenses with a deep, round tint is most effective, allowing wavelengths of low luminous efficiency for rod photoreceptors to be transmitted to the retina, while those of a higher luminous efficiency (short wavelength light) are absorbed by the filter.315,392 Although associated systemic findings are usually absent, a child with congenital achromatopsia with short stature, mild developmental delay, premature puberty, small hands and feet, minimal dysmorphism, and unilateral parental isodisomy of chromosome 14 has been described.446

In achromatopsia, cone photoreceptors are probably present but lack the full complement of protein necessary for phototransduction, making this condition potentially responsive to gene therapy (as has been demonstrated in mice and dogs). Therapeutic intervention may hold promise as subretinal gene therapy in mice has produced striking visual improvement in the GNAT2 form of achromatopsia by restoring the visual transduction cascade.266

Blue Cone Monochromatism

Blue cone monochromatism is a partial form of achromatopsia in which the blue cone mechanism predominates. The diagnosis is suggested by the presence of X-linked inheritance and high myopia in a child with achromatopsia.571 In 1957, Blackwell and Blackwell65 first described this disorder in three brothers with congenital achromatopsia who had the residual ability to discriminate blue and yellow objects. Lewis et al368 have defined two classes of mutations localized to the long arm of the X chromosome (Xq28) that are responsible

for blue cone monochromatism.368,417 These defects involve one or more regions of the contiguous red and green cone pigment genes on the terminal end of the long arm of the X-chromosome, causing affected individuals­ to have minimal functional red or green cone pigments­ .417,418 Blue cone pigments, which are coded on chromosome 7, are unaffected.

Magenta tints, which prevent rod saturation while allowing transmission of blue light, are indicated in blue cone monochromatism.253,392 Whereas the L (red) and M (green) pigment genes are located on the X chromosome, the S cone (blue) pigment is located on chromosome 7. Mutations in the L and M pigment gene array that result in the lack of functional L and M pigments, and thus inactivate the corresponding cones have been identified in most cases of blue cone monochromatism.417,418

Clinically, patients with blue cone monochromatism present with infantile nystagmus although nystagmus is occasionally absent. Gottlob and Reinecke228 believe that individuals with blue cone monochromatism and achromatopsia share an electro-oculographically distinct form of nystagmus (see achromatopsia). The finding of a fine-amplitude, upbeat, jerk-type nystagmus in carrier females with normal visual acuity raises the possibility that the nystagmus may be caused independently by the mutation in the absence of an underlying visual deficit.229 Gottlob229 found abnormal eye movements in carriers of blue cone monochromatism, suggesting that the nystagmus is intrinsic to the disease and independent of the visual defect. Some patients have tilted optic discs.

Unlike in achromatopsia, in which visual acuity is usually no better than 20/200, children with blue cone monochromatism (and other less-common forms of incomplete achromatopsia) often have acuities better than 20/200, indicating residual cone function.571 Affected patients show a preferential ability to identify blue-yellow color plates. Farnsworth Panel D-15 tests show consistent errors directed along the protan and deutan axis but not the tritan axis, in contrast to the random pattern of errors seen in complete achromatopsia.571 Unlike achromats, blue cone monochromats and their carriers do not show paradoxical pupillary defects.436 The long-term visual prognosis of blue cone monochromatism is paradoxically worse than that of complete achromatopsia as teenagers and adults develop a progressive atrophic maculopathy that secondarily reduces central acuity.200,418

ERG is useful in establishing the diagnosis of achromatopsia (minimal photopic response with preservation of scotopic response), but it does not separate out the blue cone response unless special techniques are used. Spectral sensitivity testing shows maximum sensitivity near 440 nm in the blue region, dropping rapidly at longer wavelengths.571 The basis of the better acuities in children with blue cone monochromatism compared with those with complete achromatopsia is difficult to explain because psychophysical data suggests that the center of the normal fovea is tritanopic.265 It is