Pelin Atmaca-Sonmez,
Naheed W. Khan,
John R. Heckenlively
INTRODUCTION
The average human retina consists of only 4.6 million cone photoreceptors compared to 92 million rods.[1] Nevertheless, cones function under daylight conditions and enable not only color vision, but also high visual acuity such as reading and discrimination of details. Therefore, loss of cone function is the principal reason for severe visual handicap in most retinal diseases.
Hereditary cone disorders are bilateral and usually symmetric group of disorders that are both clinically and genetically heterogeneous. They present either as pure or predominantly cone system abnormalities or as cone-rod dystrophy where rods are also affected but to a lesser extent.
Cone photoreceptor dysfunction should be suspected in patients with subnormal visual acuity in the presence of photosensitivity, light adaptation problems, difficulty with color saturation and/or discrimination, and better sight at dusk and night, since these are the typical symptoms. In addition, nystagmus is often found in early onset cone dystrophies.
Standardized full-field electroretinography (ERG) is essential for establishing the diagnosis of cone dystrophy or degneration.[1a] The diagnosis of cone dysfunction or dystrophy can be very difficult and questionable only by fundus examination, since the signs and symptoms may be subtle or mimic other conditions. Fundus findings may be normal in the early stages of the disease; however, retinal pigment epithelium (RPE) loss and pigment deposition may occur in the later stages. Mild to severe temporal optic atrophy is commonly seen in patients with cone degeneration.
Cone dystrophy implies a panretinal disorder and not a localized dysfunction, such as in macular degeneration, where the photopic ERG is normal. Cone dystrophies are characterized by a decreased or nonrecordable photopic ERG and a normal scotopic ERG. Besides using a single or averaged flash under light-adapted conditions, another technique for isolating the cone response is to employ a flickering, bright stimulus light with a frequency greater than 20-30 cycles/s (hertz). Dark adaptation test shows elevated cone thresholds but normal rod thresholds. Goldmann visual field (GVF) tests contribute to diagnosis significantly and document the visual function of the patient. Often patients with cone-rod loss patterns on the ERG and retinitis pigmentosa (RP) visual loss, can be identified on GVF. GVF is a form of kinetic perimetry where the rate of movement of the target is kept constant and, the visual field is searched for areas where a given target can be seen, unlike static perimetry where the threshold brightness of a static stimulus of a given area of the visual field is measured. Therefore, GVF is the preferred method for patients with retinal degeneration. GVF is superior also because it can screen a wider angle of visual field, which is important to detect peripheral constriction. Patients with cone dystrophies have stable peripheral visual fields but may have central scotomata. If a patient has expanding central scotomata that become larger than 20° or develop ring scotomata, then an RP type process may be present.
Taking a detailed family history is important and necessary to determine the inheritance pattern and thus, screen for appropriate gene mutations. In recent years, several genes have been linked to cone and/or cone-rod dystrophies. Nevertheless, many cases show no inheritance pattern, which indicates that there are other genes to be identified, and there may be nongenetic factors yet to be identified.
Cone disorders can be classified according to time of presentation; congenital or very early-onset, and childhood or later-onset. In general, congenital-onset disorders are stable or less progressive compared to later-onset ones. There has been little evidence suggesting the presence of later childhood retinal degeneration in congenital cone dystrophies.
CONGENITAL AND VERY EARLY-ONSET CONE DYSTROPHIES
CONGENITAL ACHROMATOPSIA (ROD MONOCHROMATISM)
Congenital achromatopsia is a rare form of primary cone disorder characterized by lack of cone photoreceptor function at or near birth with normal rod function. Patients may have partial to full expression of the disorder and it can be classified into complete and incomplete forms according to the degree of cone function.
Complete achromatopsia is a severe condition with functional absence of cone function and therefore a visual acuity in 20/200 range, very poor or no color discrimination, nystagmus and marked photophobia; whereas, in the incomplete form (atypical achromatopsia) cone ERG responses are decreased but these patients have better visual acuities (20/80 to 20/200) and color vision compared to complete forms of achromatopsia.[2] The nystagmus is typically of rapid frequency and low amplitude, and decreases in severity by the end of the first decade.[2] Patients with achromatopsia also have light adaptation problems since rods saturate at higher levels of illumination. In addition, high hyperopia may be found. Biomicroscopy shows normal anterior and posterior segment morphology. Fundus examination is initially normal, but a reduced foveal reflex or central or mid-peripheral RPE abnormalities such as pigment mottling may be seen. Foveal atrophy often develops in the later stages of the disease. The ERG shows profoundly reduced or nonrecordable cone ERGs and normal to near normal rod ERG responses. Some patients may complain of central scotoma, which can be documented by visual field testing. All the clinical findings are present in the neonatal period, and the condition is generally stable through middle age, after which some patients show mild progression of visual acuity loss from aging.
Histopathology: The number of reported human histopathologic cases is limited.[3,4] Perhaps more can be learned at this stage from the mouse models which have studied to date with cone dystrophy/achromatopsia.[4a]
Genetics: Congenital achromatopsia is inherited autosomal recessively. Up to date, mutations in three genes, all of which are involved in the cone phototransduction cascade, have been associated with congenital achromatopsia: CNGA3, CNGB3, and GNAT2 (Table 178.1).[5] CNGA3 and CNGB3 encode the ?- and ?-subunits of cone cyclic nucleotide-gated (CNG) channels, and GNAT2 encode the ?-subunit of cone-specific transducin. Mutations in CNGB3 have also been linked to progressive cone dystrophy and macular degeneration. CNGA3 accounts for 20-30%, CNGB3 for 40-50% and GNAT2 for a minor fraction of achromatopsia cases. Both the complete and the incomplete forms have been associated with CNGA3 and GNAT2 mutations, and rarely in CNGB3. A locus on chromosome 14, ACHM1, has also been linked to achromatopsia.[6]
TABLE 178.1 -- Associated Gene Mutations in Hereditary Conditions with Full or Partial Cone Disorders[5]
|
Disorder |
Gene/Loci |
Chromosome |
Phenotype |
|
Early onset |
CNGA3 |
2q11.2 |
ar Congenital achromatopsia |
|
CNGB3 |
8q21.3 |
ar Congenital achromatopsia, progressive cone dystrophy |
|
|
GNAT2 |
1p13.3 |
ar Congenital achromatopsia |
|
|
ACHM1 |
14 |
Congenital achromatopsia |
|
|
Mutations in red and green pigment genes |
Xq28 |
X-linked Blue cone monochromatism |
|
|
Late onset |
GUCA1A (COD3) |
6p21.1 |
adCOD; adCORD |
|
RDH5 |
12q13.2 |
arCOD; ar fundus albipunctatus |
|
|
COD2 |
Xq27; not cloned |
COD |
|
|
AIPL1 |
17p13.2 |
adCORD; arLCA |
|
|
CRX |
19q13.32 |
adCORD; ar, ad, de novo LCA; adRP |
|
|
GUCY2D |
17p13.1 |
adCORD; arLCA |
|
|
RIMS1 |
6q13 |
CORD |
|
|
Sema4A |
1q22 |
adCORD; adRP |
|
|
UNC119 |
17q11.2 |
CORD |
|
|
CORD4 |
17q; not cloned |
CORD |
|
|
ABCA4 |
1p22.1 |
arCORD; arStargardt disease; arRP |
|
|
CORD8 |
1q12-q24; not cloned |
CORD |
|
|
CORD9 |
8p11; not cloned |
CORD |
|
|
RPGR (CORDX1) |
Xp11.4 |
X-linked COD 1; X-linked CORD;X-linked recessive RP; X-linked dominant RP; X-linked CSNB; X-linked atrophic MD |
|
|
CORDX2 |
Xq27-28; not cloned |
X-linked CORD |
|
|
CORDX3 |
Xp11-q13; not cloned |
X-linked CORD |
|
|
COD4 |
Xp11.4-q13.1; not cloned |
X-linked CORD |
|
ar, autosomal recessive; ad, autosomal dominant; RP, retinitis pigmentosa; CSNB, congenital stationary night blindness; CORD, cone-rod dystrophy; LCA, Leber's congenital amaurosis; MD, macular dystrophy; COD, cone dystrophy. |
Case 1
A 9-month-old boy was referred to our clinic for possible Leber's amaurosis congenita due to his poor vision and nystagmus. The patient had a hypermetropic refraction of OD: +6.50 +1.50×90; OS: +6.75 +2.00×90. He fixated and followed well with both eyes. The anterior segment was unremarkable. Indirect ophthalmoscopy suggested slight fovea centralis atrophy. Standardized full-field ERG was performed which showed very low photopic b-wave and flicker amplitudes with greatly prolonged implicit times, and normal scotopic b-wave amplitudes for his age (Fig. 178.1). His family history was noncontributory. Since these findings ruled out Leber's amaurosis and suggested congenital achromatopsia, he and his mother was genotyped for the two most common achromatopsia genes, CNGA3 and CNGB3. The clinical diagnosis was confirmed when homozygous mutations in the CNGA3 gene were found.
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FIGURE 178.1 Standardized full-field dark- and light-adapted ERGs of cases with autosomal and X-linked recessive (AR CD; XL CD), and dominant cone dystrophy (DOM CD), blue cone monochromatism (BCM), and achromatopsia from CNGA3 and CNGB3 mutations. All show very low to nonrecordable photopic b-waves and flicker amplitudes with prolonged implicit times, and normal scotopic b-wave amplitudes for his age. Some cone dystrophy patients have subnormal to abnormal rod b-wave amplitudes compared to normal controls, but they will remain unchanged over time. |
Case 2
An 11-year-old girl was referred to our clinic with complaints of seeing poorly even with glasses OD: +4.00+2.00×90; OS: +3.25+3.00×90, and difficulty in adjusting to different light conditions. Her family history revealed that her mother has always had color vision problems and mild subnormal vision.
She had manifest nystagmus as an infant which became latent over time. Her best corrected visual acuity was 20/50 OD and 20/100 OS. Anterior segment examination was within normal limits. Fundus examination revealed foveal atrophy and light temporal pallor of the optic disk (Fig. 178.2a,b). The dark-adapted rod threshold testing was normal. Color vision testing with Ishihara plates was 5/15 and the Farnsworth D-15 showed a tritan pattern bilaterally. Color vision in her mother was 5.5/15 with Ishihara plates. Standardized full-field ERG recorded very low photopic b-wave and flicker amplitudes and normal scotopic b-wave amplitudes (Fig. 178.1). GVFs were within normal limits with various target sizes (Fig. 178.3).
|
|
|
|
FIGURE 178.2 Fundus photographs (a) OD and (b) OS, of a 9-year-old girl with congenital achromatopsia from mutations on CNGB3 with subtle foveal atrophy (with fie granularity) and slight temporal pallor of the optic disk. |
|
FIGURE 178.3 GVFs are an important diagnostic test for cone dystrophy patients. The isopters are always full (though myopic patients may have some attentuation), and do not have ring scotomata; many patients will show small central scotomata on careful testing. This 9-year-old case of congenital achromatopsia and was essentially normal with various target sizes for her age. |
Her clinical and electrophysiologic tests suggested incomplete achromatopsia. Therefore, she and her mother were screened for mutations in the known achromatopsia genes and the testing confirmed the clinical diagnosis by documenting homozygous mutations in the CNGB3 gene and the carrier mother was heterozygous for this mutation.
BLUE CONE MONOCHROMATISM
Blue cone monochromatism is similar to congenital achromatopsia except that the inheritance is X-linked recessive and that there appears to be an intact S (blue) cone function with the absence of L (red) and M (green) cone function confirmed by the electrophysiologic and pyschophysical testing. There has been no histological data on blue cone monochromatism up to date. Therefore, it is also named as X-linked incomplete achromatopsia. It occurs even less frequently than congenital achromatopsia.
Young males with blue cone monochromatism typically have fie to intermittent nystagmus, photophobia, reduced visual acuity, poor color vision, and myopia.[7] Visual acuity ranges from 20/60 to 20/400. Many patients with blue cone monochromatism have better visual acuity and color vision than do patients affected by achromatopsia, and the nystagmus often regresses. However, patients who are partially affected with better than 20/100 vision may lose vision with aging after the age of 40 years. Fundus examination ranges from normal to fie granular changes in the macula in males, and more obvious atrophy in the macula in some older males. Temporal optic nervehead atrophy is common. Males with this condition have a peak sensitivity near 504nm under dark-adapted conditions because of normal rod function and a peak sensitivity near 440 nm under light-adapted conditions because of normal blue cone function, in contrast to healthy males with peak sensitivity under light-adapted conditions near 555nm.
Congenital achromatopsia and blue cone monochromatism are often difficult to distinguish in males in the clinical setting. Standardized full-field ERG shows similar findings to that seen in congenital achromatopsia; the photopic ERG and 30-Hz white flicker is poor to nonrecordable, while the rod-isolated ERG is normal to subnormal. Therefore, aside from genetic analysis (X-linked inheritance pattern or mutational analysis), the diagnosis of blue cone monochromatism and differentiation from achromatopsia is made on the basis of hereditary pattern, specialized color and ERG testing. It is necessary to document blue cone function and the lack of other cone functions psychophysically for the clinical diagnosis. This can be done by the S-cone full-field ERG by using a blue flash stimulus on a yellow background.[8] A series of color vision test plates, called Berson color test, can be used to distinguish young males with X-linked blue cone monochromatism from young males with autosomal recessive rod monochromatism.[9] However, this test may not necessarily differentiate patients with blue cone monochromatism from those with cone dystrophy.[10] For practical purposes, blue cone monochromats are more likely to correctly identify the blue-yellow plates in the HRR color plate test and are less likely to make errors along the tritan axis on Farnsworth D15 test.[11] Short-wavelength specific perimetry[12] and testing the visual acuity with the use of blue and yellow filtered glasses[13] have also been used to differentiate the two disorders. In addition to these tests, it has recently been suggested that optical coherence tomography could be useful in the differentiation of congenital achromatopsia and blue cone monochromatism by reflectivity profile analysis. Foveal thickness has been found to be decreased in patients with blue cone monochromatism compared to normal subjects and patients with achromatopsia.[14]
Most carriers are clinically normal but psychophysical and electrophysiological tests may demonstrate abnormalities in color vision, delays in dark adaptation and some abnormal ERG findings such as diminished cone ERGs, mild delays in cone implicit times, and loss of the a1 oscillation to white light under dark-adapted conditions.[15] Carriers may also show a red-green deficiency on psychophysical testing. Although this condition is usually stable, progression of the disease has also been documented.[16]
Since sophisticated psychophysical testing is available only in few centers, the diagnosis is presumptive without the molecular genetic confirmation, though an X-linked pedigree is highly suggestive.
Genetics: The genes coding L and M pigment (OPN1LW and OPN1MW) are located on the long arm of the X chromosome (Xq28), whereas the S-cone pigment is encoded by a gene located on chromosome 7. Two mechanisms have been postulated for blue cone monochromatism.[17,18] One mechanism is that the mutations in L and M pigment genes result in the lack of functional pigments. The most frequent inactivating mutation disrupts the folding of cone opsin molecules.[19] Another mechanism is a disruption of the upstream locus control region that controls the transcriptional regulation of the L and M visual pigment genes.[20] These changes result in lack of functional blue cones which represent less than 10% of the cone population.[21] A third molecular genetic mechanism has been described in a single family where exon 4 of an isolated red pigment gene had been deleted.[22] Subtypes of this condition and individuals with residual L-cone or M-cone have been reported.[23,24]
CHILDHOOD AND LATER-ONSET CONE DYSTROPHY H1
Unlike the congenital and early-onset types, the later-onset cone dystrophies typically present with mild vision loss that shows progression over time. The age of onset of visual loss and the rate of progression show wide variability, but visual acuity usually deteriorates over time to 20/200 or worse.
The fundus appearance of a patient with cone dystrophy may appear normal early in the disease process; however, decreased foveal reflex, fovea centralis atrophy, and bull's eye appearance is present in most cases in later stages. Some patients with later-onset X-linked cone dystrophy have confluent areas of tapetal-like sheen.[25] These patients may also be more subject to retinal holes which should be treated, if found, to prevent retinal detachments. Color vision problems may present even before the compromise of visual acuity, which may distinguish cone dystrophy from Stargardt disease or other macular dystrophies. In early cone degenerations, the color defect is usually of the red-green type.
Full-field ERG confirms the diagnosis by showing generalized abnormality of cone function including the dark-adapted cone-mediated x-wave (the first cornea-positive wave elicited with red light), 30-Hz flicker, and photopic responses with normal or subnormal rod function. The cone b-wave implicit time is usually prolonged.
Histopathology: Histopathologic examination of eyes from a 75-year-old man with autosomal dominant cone degeneration and GUCA1A mutation showed the loss of both rods and cones in the fovea and attenuated RPE.[26] Reduced numbers of cones was observed in the parafovea, and only occasional cones were visible in the periphery, whereas rods were preserved in the periphery. Another histopathological study of donor eyes from an 85-year-old affected member of a clinically well-characterized family with an autosomal dominant cone dystrophy with no known mutation showed that the cone pedicles appeared larger than normal both in the macula and periphery.[27] An abnormal distribution of cone red and green opsins was observed, and the blue cone opsin displayed restricted distribution to cone outer segments compared to matched control eye.
Eyes of an 84-year-old man from a family with X-linked cone degeneration in which affected members have a 6.5-kilobase deletion in the red cone pigment gene were studied histopathologically.[28] At his most recent ocular examination, at age 71 years, this patient had a visual acuity of 20/200 OU, fundus changes suggestive of macular degeneration, borderline-normal full-field rod ERGs, and profoundly reduced full-field cone ERGs. Histopathologic examination demonstrated marked loss of cone and rod photoreceptors and the retinal pigment epithelium in the central macula. The peripheral cone population was reduced, while the peripheral rod population was relatively preserved. Immunohistochemical examination disclosed a prominent loss of the red and green cone population and preservation of the blue cone population. These findings show that a defect in the red cone pigment gene can result in extensive degeneration of the red and green cone population across the retina.[29]
Genetics. A number of genes or loci have been linked to cone dystrophy with three main Mendelian inheritance patterns: Autosomal dominant: GUCA1A; autosomal recessive: RDH5; and X-linked recessive: RPGR, and COD2 (Table 178.1). Many cases have no family history.
GUCA1A encodes GCAP1 (guanylate cyclase-activating protein 1) which is a Ca2+-binding protein involved in the replenishment of cGMP in rods and cones. The main functional consequence of three dominant mutations (Y99C, E155G, and I143NT) has been shown to be a loss of Ca[2+] sensitivity as a result of cGMP overproduction.[30] Mutant GCAP1 protein activates retinal guanylate cyclase-1 (RetGC1) at low Ca[2+] concentrations, but fails to inactivate at high Ca[2+] concentrations, thereby leading to the constitutive activation of RetGC1 in photoreceptors.[31] The consequent dysregulation of intracellular Ca[2+] and cGMP levels is believed to lead to cell death.
GUCY2D. Kelsel et al localized an autosomal dominant cone-rod degeneration, called CORD6, to 17p13 and found that the mutation was in the retinal guanylate cyclase (GUCY2D) gene which cause an inability to regenerate cyclic guanosine monophosphate (cGMP).[31a,31b] GUCY2D mutations were initially described in a North African family with Leber congenital amaurosis (LCA1),[31c,31d] but mutations in the GUCY2D gene also have been found causing cone-rod degeneration. It has been shown that activated retinal guanylate cyclase GUCY2D functions to restore cGMP levels in photoreceptor cells in light-adapted states.[31e,31f] GUCY2D is activated by guanylate cyclase activation protein (GCAP-1) which is inhibited by increased intracellular Ca+ levels, which occurs during dark adapted states.
Case 3 GUCY2D (P575l) Mutation
This African-American female was first examined at age 22 with a complaint that her central vision had been slowly failing since age 12. The medical history was unremarkable except for visual problems. On examination the best corrected visual acuity was 20/300 OU. Funduscopy showed an area of discrete macular RPE atrophy OU and the fluorescein angiogram revealed hyperfluorescence of a window defect in the area of the macular RPE loss (Fig. 178.4). The photopic ERG was nearly extinguished (Fig. 178.1, AD CD), and the flicker fusion test was of abnormal amplitude but recordable to 60 flashes/s OU The scotopic ERG and the dark adaptation fial rod threshold were normal. Color vision testing with the Nagel anomaloscope revealed an abnormally wide equation with a protanomalous axis and with a severe luminosity loss. The GVFs were within normal limits. Color vision testing with Ishihara plates was 0/14 OU.
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FIGURE 178.4 The 22-year-old female with a GUCY2D autosomal dominant mutation. Visual acuity was 20/300 OU. Fundus photography shows a granular atrophic process in the macular while the fluorescein angiogram on the left has a sharply defied loss of the macular RPE which was not as apparent on clinical exam or fundus photography. |
RDH5 plays a role in the conversion of 11-cis-retinol into 11-cis-retinal in the RPE. RDH5 mutations have also been associated with fundus albipunctatus.
Mutations in the RPGR gene (RP3), also named as RP GTPase regulator, is the most common cause of X-linked RP (XLRP) and have also been linked to cone and cone-rod dystrophies,[32] recessive atrophic macular degeneration,[5] hearing loss, sinusitis and chronic recurrent respiratory tract and ear infections.[33,34] In addition to the axoneme, the RPGR-ORF15 protein is localized to the basal bodies of photoreceptor connecting cilium.[35] Studies suggest that RPGR-ORF15 is involved in microtubule organization and regulation of transport in primary cilia.[36] RPGR may also be an exchange factor for an unknown GTPase.
It is currently not known why mutations in the above mentioned genes that encode proteins both in rods and cones result in predominant cone disease.
CONE-ROD DYSTROPHIES
The term 'cone-rod' derives from the standardized full-field ERG pattern in which the b-wave amplitude of the cone-isolated, or photopic ERG is more affected than the rod ERG. Dark adaptation and GVF tests also contribute to determine the diagnostic pattern. Hereditary cone-rod dystrophies should not be confused with a subset of RP patients in whom cones are affected proportionately more than rods and whom have typical findings of RP.[37] These two entities are both genetically and clinically distinct, although it may sometimes be difficult to differentiate unless a GVF is performed, which can be repeated on several occasions if there is any question about the category of diagnosis. The ERG diagnostic pattern alone may not give a complete picture in some cases where there is mixed cone and rod loss.
Patients with cone-rod dystrophy experience progressive deterioration in central vision, and light and dark adaptation, mild photophobia, and may have moderate to high myopia.[37] Fundus examination usually shows variable findings such as macular atrophy, bull's eye lesion, peripheral retinal degeneration, RPE mottling, and extensive chorioretinal atrophy, in addition to findings of myopia. In cone-rod dystrophy, mild bone spicule or clumped pigmentation and retinal arteriolar narrowing can be found, which are also seen in RP. Patients with cone-rod dystrophy have diminished visual acuity, normal or diminished color vision, monophasic dark-adaptation curves with slightly elevated rod thresholds, markedly reduced cone ERGs. Visual field defects include central/paracentral scotoma, ring scotoma, generalized depression of sensitivity, and constriction of peripheral fields.
The distinction between cone dystrophy versus cone-rod dystrophy versus the cone-rod degeneration of RP is important in that the prognosis for retaining useful peripheral vision is, as expected, worse in the latter.
Carriers of X-linked cone-rod dystrophy may appear clinically normal or may be identified by subtle color vision defects, fundus abnormalities, prolongation of the 30-Hz flicker implicit time or an abnormal flattened photopic a-wave.[38]
Histopathology: The eyes with cone-rod dystrophy showed loss of cone photoreceptors throughout the retina, most pronounced in the macula and far periphery, with relative preservation of cone numbers in the midperiphery.[39] Most cone and rod outer segments were slightly shortened, but rods were otherwise morphologically normal throughout the retina. The most prominent change in the retina was the enlarged, distorted shape of the cone pedicles, which contained reduced numbers of synaptic vesicles.
Histopathologic study of a 69-year-old man with X-linked cone-rod dystrophy associated with an RPGR-ORF15 mutation revealed an atrophic macula with bull's eye appearance, focal absence of RPE in the macula, and pigmentary changes elsewhere.[40] Cones and rods were absent at the perifovea and were reduced with shortened outer segments elsewhere in the macula. In the remainder of the retina, cones but not rods were reduced and all photoreceptor outer segments were shortened.
In addition, cone system postreceptoral changes such as swollen and pale Müller cell processes and abnormality in the outer plexiform layer processes have been reported.[39] The negative ERG seen in some cone dystrophy patients support these histopathological findings.[41]
Genetics: Mutations in several genes or loci have been linked to cone-rod dystrophies with autosomal dominant, recessive and X-linked inheritance (Table 178.1).
RIMS1 encodes a rab3A-interacting molecule (RIM, also named as regulating synaptic membrane exocytosis protein 1) that is expressed at presynaptic zones in brain and photoreceptors, where neurotransmitters are released.[42] The protein localizes to ribbon synapses and interacts with RAB3A, a protein that regulates synaptic vesicle exocytosis.
UNC119 encodes a highly enriched protein found also in the photoreceptor ribbon synapses and has been associated with late-onset cone-rod dystrophy.[43]
Sema4A is a member of a large transmembrane protein family known as semaphorins that are involved in angiogenesis, organ development, and immune system functions. Sema4A is expressed in ganglion cells, inner retinal neurons, and RPE cells and functions as a transmembrane ligand for a receptor present on photoreceptors.[44] Different mutations in the Sema4A have been associated with autosomal dominant retinitis pigmentosa (adRP) as well as cone-rod dystrophy.[45]
RPGR-ORF15, which has been associated with XLRP, has also been linked to X-linked cone-rod dystrophy. Cone-rod dystrophy patients with RPGR-ORF15 mutations tend to have a later onset of visual loss compared to patients who have CORDX2 and CORDX3 mutations.[45a,45b] In addition, a parafoveal ring of increased fundus autofluorescence was reported to be an early indicator of affected status in these patients.[46]
AIPL1 encodes arylhydrocarbon-interacting receptor protein-like 1 (AIPL1), which is expressed in both developing cone and rod photoreceptors, but it is restricted to rod photoreceptors in the adult human retina. AIPL1 appears to play a role in the regulation of the cell cycle or cell growth for proteasomal degradation,[47,48] and may also function as a potential chaperone for phosphodiesterase.[49,50]
The gene, GUCY2D, expresses the protein retinal-specific guanylate cyclase, RETGC1, in the outer segments of cones and to a lesser degree in rods, which is an essential component of the phototransduction cascade by maintaining intracellular cGMP levels. Mutations in RETGC1 impair the recovery of the dark state after photo-excitation of the photoreceptor cells.[51]
While recessive mutations of GUCY2D and AIPL1 have been associated with LCA, dominant mutations in these genes have been found in patients with cone-rod dystrophy.
CRX (cone rod homeobox) is expressed in rod and cone photoreceptors, horizontal cells and inner nuclear layer neurons in the retina and cells within the photosensitive pineal gland in mammals. It is a key transcriptional regulator of photoreceptor-specific gene expression such as PDE6A,[52] and possibly RP1, GUCY2D and ABCA4.[53]
ABCA4 encodes the protein, ABCR (ATP-binding cassette transporter-retinal) for Stargardt's disease, which is expressed in the rims of the rod and cone outer segment disks[54] and is involved in translocation of the phospholipid complex out of the disk membrane into the cytoplasm. When this recycling process fails due to mutations, N-retinylidine-phosphatidylethanolamine accumulates in the photoreceptor outer segments. Most Stargardt's disease patients have cone-rod dysfunction patterns on the ERG.[54a]
DIFFERENTIAL DIAGNOSIS
Misdiagnosis of cone dystrophy is common in the absence of standardized electrophysiological testing. The differential diagnosis of cone dysfunctions is summarized in Table 178.2 and includes hereditary cone dystrophies, hereditary cone-rod dystrophies, cone-rod degeneration, and cone-rod forms of RP.
TABLE 178.2 -- Differential Diagnosis of Cone Dysfunctions
|
Hereditary cone dystrophies |
|
Hereditary cone-rod dystrophies |
|
Congenital color vision abnormalities without retinal degeneration (protanopia, deutranopia and tritanopia) |
|
Congenital nystagmus (cone dystrophy must be ruled out) |
|
Leber's amaurosis congenita |
|
Ocular albinism |
|
Cerebral achromatopsia |
|
Cone-rod degeneration (type II) retinitis pigmentosa |
|
Acquired cone dysfunctions (e.g., chorioretinitis) |
|
Conditions with Bull's eye maculopathy (drug toxicity (e.g., chloroquine, hydroxychloroquine, clofazimine, digoxin), Stargardt's disease/fundus flavimaculatus, lipofuscinosis, fucosidosis, fenestrated sheen macular dystrophy, juvenile Batten's disease, central areolar choroidal dystrophy) |
Cone or cone-rod dystrophies tend to be relatively stationary in terms of peripheral visual fields, but may have central/paracentral scotomata, which can show progression.[55-57] On the other hand, RP patients with cone-rod degeneration pattern, typically are not as night blind and often note night blindness late in the disease, show progressive loss of visual field, ring scotomata tighter to fixation than patients with rod-cone forms of RP, and the different isopters on the GVF are adjacent to each other like an onion ring in many cases.[55]
Cone dystrophies should be distinguished from the congenital color vision abnormalities (protanopia, deutranopia, and tritanopia) which are not associated with retinal degeneration.
The congenital-onset cone dystrophies often are initially misdiagnosed as congenital nystagmus, Leber's amaurosis congenita, and ocular albinism but standardized electrophysiological testing will quickly help with the correct diagnosis.
In addition, some acquired conditions such as presumed chorioretinitis or inflammatory insults to retina may result in asymmetric and relatively stable cone-rod degeneration. It should also be noted that cones eventually undergo degeneration in diseases where rods are primarily affected because rods enable cone survival.[58]
The inheritance pattern and the progress of the disease, age at onset of visual loss, fundus findings and electrophysiologic and GVF tests help to differentiate these entities.
MANAGEMENT
Although currently there is no cure for any of the cone dystrophies, there are still ways to help these patients for better vision. First of all, it is essential that the correct diagnosis is made so that genetic counseling can be offered to determine the risk of passing on the disease to the offsprings and within the family and that patients can be accurately informed on their conditions and the long-term visual prognosis. It is important to inform the patients that although the central vision is affected, peripheral vision is most likely to be retained in this condition.
Patients with cone disorders suffer from photophobia and their vision decreases as levels of illumination increases. Therefore, different density tinted lenses and sunglasses for varying conditions are necessary to maintain a reasonable amount of vision in these patients and also to protect the retina from potential light toxicity.[59] It has been reported that the achromatopsia patients are likely to benefit most from deep red tinted glasses, and the blue cone monochromats most from magenta tints.[59-61] Some patients, especially the ones with nystagmus, may benefit more from the use of red contact lenses due to complete pupillary coverage which limits peripheral glare, reduces optical surfaces, and eliminates rear surface reflections.[62] The contact lens system (ChromaGen) that is designed to enhance color perception in color vision deficiency may enhance subjective color experience and assist in certain color-related tasks, but may adversely affect vision in dim light and judgment of distance and motion.[63]
Since refractive errors are frequently seen in patients with cone dystrophy, these patients should be followed regularly for the correction of refractive errors.
There is no direct evidence that any drug therapy is beneficial in cone dystrophies; however, apoptosis appears to be the fial common pathway in hereditary retinal degenerations[64] and therefore antioxidants such as carotene (nonsmokers), lutein, vitamin C and vitamin E may be useful in ameliorating the photic injury and slowing the degeneration.[65,66] Many patients will benefit from low vision aids such as magnifiers, closed-circuit televisions, and specialized software for enlargement of text displayed on computer screens.
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