Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Retinal Disease_Wright, Spiegel, Thompson_2006

162 HANDBOOK OF PEDIATRIC RETINAL DISEASE

Cone Dystrophies

The cone dystrophies, like the rod-cone dystrophies, represent a heterogeneous group of diseases. Cone dystrophies and cone-rod dystrophies can be inherited in an autosomal dominant, autosomal recessive fashion, or X-linked fashion.

The diagnosis of cone dystrophy is suggested by a history of central acuity loss and poor color discrimination, often accompanied by nystagmus, severe photophobia, and photoaversion. Cone–rod dystrophies are essentially the reverse of rod–cone dystrophies or RP in that they are progressive retinal dystrophies but begin with central vision loss and cone dysfunction rather than peripheral loss and dark adaptation difficulties. Ophthalmoscopy may show a symmetrical “bull’s-eye” pattern of macular atrophy, particularly in the autosomal dominant form, although this clinical picture is not specific (see Chapter 13 for the differential diagnosis of “bull’s-eye” macula). A more diffuse atrophy of the retina and retinal pigment epithelium in the macula may be seen in the autosomal recessive forms.48 Electroretinography shows selective loss of cone function, which helps distinguish macular pigmentary changes in cone dystrophy from Stargardt’s disease and fundus flavimaculatus.

Rod involvement may eventually become evident on ERG, and perimetry may show constricted visual fields or ring scotoma.84,122 Ophthalmoscopy at later stages often shows bone spicule-like hyperpigmentation and atrophy in the periphery similar to typical rod–cone degenerations. If severe, symptoms of nyctalopia may be found. The latter are often called cone–rod dystrophies to describe the predominant cone involvement with accompanying rod dysfunction.

Other patterns of cone dysfunction have been reported in which full-field ERG results appear normal. Selective central or peripheral cone involvement has been documented.85,112,122 The more typical cone dystrophies described previously may also show telangiectasias of the optic nerve head and temporal disc pallor as well.63 Early in the course of the disease, cone–rod dystrophy may appear to resemble Stargardt disease. The former is progressive whereas the latter is not; therefore, documentation of a stable ERG is necessary for a definitive clinical diagnosis of Stargardt disease.

Autosomal dominant cone–rod dystrophy is caused by mutations in the guanylate cyclase 2D gene (GUCY2D) on

chromosome 17p, the RDS/peripherin gene on 6p12, GUCA1A on 6p21, CRX on 19q, and three other loci on 6q and 17q.33

Dyschromatopsias (Color Blindness)

Normal males have one normal red pigment gene and one to three green pigment genes in a tandem array on their single X chromosome. Unequal homologous recombination during meiosis can give rise to a variable number of green pigment genes yet still produce a complement with normal color vision. Congenital dyschromatopsias (inherited disorders of color vision) result from either a complete loss of red or green pigment genes or a hybrid red-green pigment gene whose spectral characteristics are anomalous.109 Acquired dyschromatopsias (disorders of color vision caused by disease) are probably related to selective loss of function of cone photoreceptors or their associated higher-order neurons.61

The ophthalmologist is often asked to evaluate a child’s color vision because of poor performance on certain color-related tasks, or positive family history, or to aid in diagnosing an ocular condition. Color vision testing in children is a challenge. Many children misname colors early in life despite normal vision (this is a common cause of requests for color vision testing). The standard Ishihara plates can be used to screen children on a routine basis. Even if a child cannot yet identify numbers, he or she can be asked to trace the numbers on the plates. The Ishihara plates only test for red-green deficiency and may therefore miss patients with blue-yellow defects. For this reason, they are most useful for detecting congenital dyschromatopsia. The Hardy Rand Rittler plates detect yellow-blue defects and utilize shapes instead of numbers. The D-15 test detects a broad range of color defects but may be more difficult for younger children because it involves matching similar colors. A gross evaluation of color vision may be obtained by having children match pieces of colored yarn or other objects.

The most common cause of defective color vision in childhood is a congenital dyschromatopsia. These disorders are classified according to the types of cone pigments present. Trichromats possess all three types: red, green, and blue. Dichromats have only two of the three pigments and monochromats only one. The terminology becomes complex when naming the associated color vision defects; protanomaly (a “defect of the first type”) is a loss of red sensitivity,

deuteranomaly (“defect of the second type”) a loss of green, and tritanomaly (“defect of the third type”) a loss of blue. If the loss of sensitivity is complete, the suffix changes to “opia,” for example, from protanomaly (partial loss of red sensitivity) to protanopia (complete loss of red sensitivity). Sophisticated testing is often necessary to exactly categorize a given defect. The most common types are X-linked deuteranomaly, deuteranopia, and protanopia. Approximately 6% of Caucasian males have this form of dyschromatopsia, which can often be diagnosed by Ishihara plates. Inherited tritanomaly and tritanopia are much more rare (0.005% of the population) and are autosomal dominant. Visual acuity is normal in these entities.

Complete achromatopsia (rod monochromatism) is a rare autosomal recessive condition. Individuals are truly “colorblind,” interpreting the world in shades of gray. The Sloan achromatopsia test is a good test to aid in this diagnosis but may be difficult to perform in children. This condition usually presents with nystagmus and marked photophobia in early childhood, with color vision defects demonstrated later in life when the child can cooperate. Visual acuity is poor, usually in the 20/200 range. Darkly tinted lenses may improve visual function, even indoors. Achromatopsia is caused by mutations in the CNGA2 gene, which encodes the alpha-subunit of the cone photoreceptor cGMP-gated channel,146 and in the CNGB3 gene, which encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel that generates the light-evoked electrical responses of the cones.134 The latter is the cause of achromatopsia in the Pingelapese islands.

Incomplete achromatopsia (blue cone monochromatism) is a condition in which patients have only short-wavelength, blue cones that function normally. There are nonhomologous deletions near the beginning of the red and green genes, which inactivates production of these two pigments.110 Deletions of the locus control region upstream of the red and green pigment genes, deletions of red pigment exons, and point mutations in isolated pigment genes caused by rearrangements have all been reported.6,86 It is inherited as an X-linked recessive condition and features males with poor vision from birth, ranging from 20/60 to 20/200 vision. Retinal pigmentary changes and a slow decrease in visual acuity may be seen over time in adulthood. The Berson color vision test may be used to distinguish blue cone monocromatism from complete achromatopsia.17 Carrier

females may have subtle ERG and eye movement abnormalities.15,56 The differential diagnosis for these conditions includes albinism, CSNB, and congenital motor nystagmus. The latter may be X linked, but maps to a different locus.79a Acquired color vision loss may be caused by seizure medication such as vigabatrin and carbamazepine, toxins such as styrene, and combinations of substances such as melatonin, zoloft, and high-protein diet.89,113,137

OTHER RP-LIKE RETINAL DISORDERS

Unilateral Pigmentary Retinopathy

Most investigators believe that the concept of unilateral retinitis pigmentosa is flawed and favor the term unilateral pigmentary degeneration. Unlike classic RP, there is usually no family history, and the onset of the disease is relatively late. Although a few cases of rhodopsin-associated ADRP may present with a falsely negative family history, mild functional involvement, and very asymmetrical retinal changes, unilateral retinal pigmentary degeneration in a child should not be considered RP unless all other possible diagnoses have been excluded. Although typical retinitis pigmentosa may exhibit some degree of asymmetrical involvement, both eyes manifest the disease. Strict criteria for the diagnosis of unilateral pigmentary degeneration demand that the fellow eye have a normal ophthalmoscopic appearance, as well as psychophysical and electroretinographic function that does not deteriorate over time.28

Reported causes for unilateral pigmentary degeneration include trauma, a transient ophthalmic artery occlusion,28 longstanding serous detachment of the neurosensory retina from an optic pit,120 asymmetrical Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex virus (TORCH) infections, and retained intraocular foreign body.8,29 The inflammatory response to a subretinal parasite known as the diffuse unilateral subacute neuroretinitis (DUSN) syndrome54 could be added to the differential diagnosis of unilateral disease. A careful birth and prenatal history should be taken, because retinopathy of prematurity is often asymmetrical and may leave retinal pigmentary changes in one eye as a result of either the disease or the treatment.

X-Linked Juvenile Retinoschisis

The diagnosis of X-linked juvenile retinoschisis is usually made on the basis of ophthalmoscopy and an X-linked recessive pattern of inheritance. Children with this disease usually come to attention because of decreased vision on school screening or acute vision loss from vitreous hemorrhage. Foveal retinoschisis is found in nearly all cases, with peripheral retinoschisis present in 50% of cases. Atrophic macular lesions are rarely seen. The vitreous body is optically empty or contains dense bands. Red-free photographs are often useful to diagnose foveal retinoschisis, and a lack of dye leakage on fluorescein angiography can help make the correct diagnosis if cystoid macular edema is erroneously suspected as the cause of poor vision. Electroretinography should be performed and generally shows a selective loss of the b-wave amplitude. In spite of an apparent selective foveal involvement by ophthalmoscopy in 50% of cases, involvement of the full-field electroretinogram suggests panretinal disease. In addition to predominant b-wave loss, dysfunction of the inner retinal layers is suggested by markedly reduced oscillatory potentials.104 The XLRS1 gene on Xp22 has been found to harbor mutations in this disorder.18

OTHER SYNDROMES

The Goldman–Favre syndrome is a very rare autosomal recessive condition, reported mainly in the European literature. Affected patients typically complain of nyctalopia and have an “optically empty” vitreous with a nonrecordable ERG.46 It is the most severe form of enhanced S-cone syndrome caused by mutation of the nuclear receptor gene, NR2E3.60a Patients with gyrate atrophy present with nyctalopia at 20 to 30 years of age and have poorly recordable rod and cone ERGs with constricted visual fields. They are usually myopic, with cataracts and characteristic nummular areas of chorioretinal atrophy. Pedigree analysis suggests autosomal recessive inheritance. Biochemical studies reveal hyperornithemia and a reduction in ornithine alphaaminotransferase activity. Dietary modifications ameliorate the disease.138,144 Affected males with the X-linked disorder choroideremia usually complain of nyctalopia between 20 and 30 years of age and may have a fundus appearance at some stages of the disease similar to patients with gyrate atrophy. Deterioration of

the RPE and choroid is progressive and does not feature extensive pigmentary clumping, as is typical in RP. ERGs are markedly affected early in life as are the visual fields.128 The preponderance of male involvement within the pedigree and the characteristic radial, “splattered mud” pattern of hyperpigmentation in the periphery of carrier females helps distinguish this X-linked recessive disease from gyrate atrophy. The choroideremia gene (CHM) has been identified and maps to Xq21.2.32 Gyrate atrophy is AR and is caused by mutations of the ornithine aminotransferase gene on 10q26.102 Spinocerebellar ataxia type 7 (SCA7), also called olivopontocerebellar atrophy type III, may present as a retinal degeneration in infancy or childhood. It is usually accompanied by ophthalmoplegia, ataxia, and progressive neurological deterioration. This disorder is autosomal dominant and maps to chromosome 3p. Expansions of CAG repeats in the gene affect the protein product, ataxin 7. Normal alleles have from 7 to 16 repeats whereas abnormal alleles have more than 41.58 The more repeats present, the worse the disease, and because repeats tend to increase with succeeding generations, especially if transmitted by the father, the disorder may be worse with each generation. Parents should be examined closely for subtle maculopathy or mild ataxia.

SUMMARY

The application of molecular biology to clinical medicine is a relatively recent development but has already had great impact upon our understanding of disease processes. It has improved our ability to care for RP patients by allowing us to establish a diagnosis of ADRP, even when clinical suspicion may be low, as well as to remove the fear of disease from unaffected relatives. Refinement in the diagnosis of simplex cases, where no family history is available, is now possible for many retinal dystrophies using molecular genetic techniques to identify abnormal candidate genes. Early success in treating retinal degenerations in animals give us hope that advances in the molecular understanding of retinal degenerations can soon be translated into more effective treatments for these diseases.

Acknowledgments. The text and figures in this chapter were derived largely from those prepared by Alan E. Kimura, MD,

Arlene Drack, MD, and Edwin M. Stone, MD, PhD, in the previous edition of this textbook. Dr. Drack is supported by the Georgia Lions Children’s Eyecare Center.

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