Inherited retinal disorders

Chapter 44 Inherited retinal disorders

Stationary retinal dysfunction syndromes

These include the forms of stationary night-blindness (rod dysfunction syndromes) and the cone dysfunction syndromes (stationary cone disorders).

Stationary night-blindness (rod dysfunction syndromes)

There are three main forms of stationary night-blindness; in congenital stationary night-blindness (CSNB) the fundus is normal or shows myopic changes. Fundus albipunctatus and Oguchi’s disease have a distinctive fundus appearance.

Congenital stationary night-blindness


International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERGs should be performed. This may not be possible in infants in whom a modified protocol is used (see Chapter 8). Four main responses are defined: a rod-specific ERG and a bright flash response performed under scotopic conditions, and two measures of cone function, a 30 Hz flicker ERG and a single flash photopic ERG. Both complete and incomplete CSNB show a “negative ERG”: the photoreceptor-derived a-wave in the bright flash response is normal, but there is selective reduction in the inner nuclear derived b-wave, such that it is smaller than the a-wave, indicating predominantly inner retinal dysfunction. In complete CSNB there is no detectable rod-specific ERG and a profoundly negative bright flash response. Cone ERGs show subtle abnormalities reflecting ON bipolar cell dysfunction (Fig. 44.2). There is a detectable rod-specific ERG in incomplete CSNB, and a profoundly negative bright flash response. Cone ERGs are much more abnormal than in complete CSNB, reflecting involvement of both ON- and OFF bipolar pathways. They show the characteristic triphasic appearance in the flicker response (see Fig. 44.2).


Fig. 44.2 Congenital stationary night-blindness. The left hand column traces (A) show data from a patient with “incomplete” CSNB (iCSNB); the center traces (B) are from a patient with “complete” CSNB (cCSNB); the right hand column traces (C) are from a representative normal subject. In iCSNB the rod ERG (DA 0.01) is mildly subnormal. The bright flash response (DA 11.0) is electronegative, with a normal a-wave confirming normal photoreceptor function, but a profoundly reduced b-wave. The 30 Hz flicker ERG (LA 30 Hz) is markedly subnormal and clearly shows the delayed double peak characteristically seen in iCSNB. The photopic single flash ERG (LA 3.0) shows marked reduction in the b : a ratio with simplification of the waveform and loss of the photopic oscillatory potentials, shown on ON-/OFF- response recording (200 ms orange stimulus on a green background) to reflect involvement of both ON- (depolarizing) and OFF- (hyperpolarizing) cone bipolar cell pathways. The PERG (pattern electroretinogram) is mildly subnormal in keeping with mild macular dysfunction. In cCSNB there is no detectable DA 0.01 response and the profoundly electronegative DA 11.0 ERG confirms the site of the dysfunction to be post-phototransduction. The LA 3.0 response shows a distinctive broadened a-wave and a sharply rising b-wave with a reduced b : a ratio and lack of photopic oscillatory potentials. This appearance indicates marked dysfunction of cone ON- bipolar cell pathways but preservation of the OFF- pathways. The profoundly negative ON- response, with preservation of the ON- a-wave and loss of the ON- b-wave, accompanied by a normal OFF- response supports this proposal. The broadened trough of the 30 Hz flicker ERG with a sharply rising peak is a manifestation of the same phenomenon. The PERG is almost undetectable. Overall, the findings in cCSNB are those of loss of ON- pathway function in both rod and cone systems.

ERG evidence of inner retinal rod system dysfunction may also occur in AD CSNB but in association with normal ISCEV cone ERGs. In other cases of AD CSNB, ERG rod responses are attenuated with normal cone responses, but the standard bright flash response does not have a negative waveform.

Molecular genetics and pathogenesis

X-linked CSNB

Two causative genes (CACNA1F and NYX) have been identified accounting for most families with XL CSNB. Incomplete CSNB is associated with mutation in CACNA1F, which encodes the retina-specific α1F-subunit of the voltage-gated L-type calcium channel. The expression of CACNA1F appears limited to photoreceptors and is prominent in the synaptic terminals. Most mutations are inactivating truncation sequence variants. The loss of functional channels impairs the calcium flux into rod and cone photoreceptors required to sustain tonic neurotransmitter release from presynaptic terminals. This results in the inability to maintain the normal transmembrane potential of bipolar cells, so the retina remains in a partially light-stimulated state, unable to respond to changes in light-levels.

Complete CSNB is associated with mutation in NYX, the gene encoding the leucine-rich proteoglycan nyctalopin. Leucine-rich repeats are believed to be important for protein interactions, with many of the mutations identified within these repeats. Nyctalopin is expressed in photoreceptor inner segments, outer and inner nuclear layers, and ganglion cells. Nyctalopin may guide and promote the formation and function of the retinal ON- pathway.

Several genotype–phenotype studies have been performed in individuals with either CACNA1F or NYX mutations. There is considerable inter- and intra-familial phenotypic variability associated with CACNA1F mutations, even with an identical sequence variant,1 suggesting that other genetic or environmental factors modify the phenotype. Although most patients with XL CSNB have non-progressive disease, Nakamura et al. reported two brothers with a CACNA1F mutation and progressive decline in vision with eventually undetectable rod and cone ERGs.2 We have also infrequently observed slow progression in patients with XL CSNB. Patients with complete CSNB (NYX mutations) are invariably myopic and have more pronounced night-blindness.3

Oguchi’s disease

Fundus albipunctatus

Electrophysiology and psychophysics

Dark adaptation is severely delayed in fundus albipunctatus (FA), reflecting abnormal regeneration of rhodopsin. The rod-cone break is delayed and full rod adaptation may take many hours. Rod ERGs are markedly abnormal, with the rod-specific ERG (DA 0.01) being undetectable under standard conditions, but becoming normal following prolonged dark adaptation (Fig. 44.4). The dark-adapted bright flash ERG (DA 11.0), which after standard dark adaptation arises in dark-adapted cones, can have a low b : a ratio; a red flash stimulus under dark adaptation shows a normal cone component but an undetectable rod component and prevents confusion with a form of CSNB associated with a negative ERG. To confirm the diagnosis of FA it is necessary to exceed the ISCEV ERG standard recommendations for dark adaptation considerably. Most but not all patients with RDH5 mutations show full recovery of rod function with extended dark adaptation. This contrasts with the findings in retinitis punctata albescens (see below), related to mutation in RLBP1, and usually allows the distinction between the two disorders.

There are two forms of FA, one in which cone ERGs are normal, and a rarer form described as fundus albipunctatus with cone dystrophy and negative ERG.9

Stationary cone disorders (cone dysfunction syndromes)

The cone dysfunction syndromes include congenital color vision disorders where there is normal visual acuity but defective color vision, and the various forms of cone dysfunction associated with reduced central vision and often nystagmus and photophobia (Table 44.1).13

Complete achromatopsia (rod monochromatism)

Molecular genetics and pathogenesis

Achromatopsia is recessively inherited and genetically heterogeneous. Four genes have been identified, CNGA3, CNGB3, GNAT2 and PDE6C; all encoding components of cone phototransduction.

CNGA3 and CNGB3 code for the α- and β-subunits of the cGMP-gated (CNG) cation channel in cone cells, respectively. In the dark, cGMP levels are high in cone photoreceptors, therefore enabling cGMP to bind to the α- and β-subunits of CNG channels, resulting in them adopting an open conformation and permitting influx of cations, with consequent cone depolarization. When light is applied, activated photopigment interacts with transducin, a three-subunit guanine nucleotide binding protein, stimulating the exchange of bound GDP for GTP. The cone α-transducin subunit (encoded by GNAT2), which is bound to GTP, is then released from its β- and γ-subunits and activates cGMP-phosphodiesterase by removing the inhibitory γ-subunits from the active site of this enzyme, which is formed by two α-subunits (encoded by PDE6C). cGMP-phosphodiesterase lowers the concentration of cGMP in the photoreceptor, which results in closure of cGMP-gated cation channels.

More than 60 disease-causing mutations in CNGA3 have been identified in patients with achromatopsia; with four mutations (Arg277Cys, Arg283Trp, Arg436Trp, and Phe547Leu) accounting for approximately 40% of all mutant CNGA3 alleles.19 By comparison, far fewer mutations have been identified in CNGB3; with the 1 base-pair frameshift deletion, 1148delC (Thr383fs), accounting for up to 80% of CNGB3 mutant disease chromosomes.20,21 The majority of CNGA3 mutations identified to date are missense mutations, indicating that there is little tolerance for substitutions with respect to functional and structural integrity of the channel polypeptide. In contrast, the majority of CNGB3 alterations are nonsense mutations.

About 70% of achromatopsia results from mutations of CNGA3 and CNGB3, with GNAT2 and PDE6C each accounting for less than 1%;19,20,21 further causative genes remain to be discovered.

Incomplete achromatopsia

Molecular genetics and pathogenesis

As in the complete form, mutations in CNGA3 have been identified in individuals with incomplete achromatopsia.19 The mutations identified are all missense mutations, located throughout the channel polypeptide including the transmembrane domains, ion pore, and cGMP-binding region. Only three of these, Arg427Cys, Arg563His, and Thr565Met, are exclusively found in patients with incomplete achromatopsia.19 Therefore, in the majority of cases of incomplete achromatopsia, other factors may influence the phenotype such as modifier genes or environmental factors. The missense variants identified in incomplete achromatopsia must be compatible with residual channel function since the phenotype is milder than in complete achromatopsia. Mutations in PDE6C have also been identified in incomplete achromatopsia.22

Mutations in CNGB3 or GNAT2 have not been reported in association with incomplete achromatopsia. However all GNAT2 mutations to date, and the vast majority of CNGB3 mutants, result in premature termination of translation, and thereby truncated and probably non-functional phototransduction proteins. Therefore an incomplete achromatopsia phenotype is unlikely to be compatible with these genotypes, which are predicted to encode mutant products lacking any residual function.

S-cone monochromatism (blue cone monochromatism)

Molecular genetics and pathogenesis

Mutation analyses have established the molecular basis for BCM.24 The mutations in the L- and M-opsin gene array cause BCM to fall into two main classes:

The data suggest that 40% of BCM genotypes are a result of a one-step mutational pathway that leads to deletion of the LCR. The remaining 60% of BCM genotypes comprise a heterogeneous group of multi-step pathways. Studies have not detected the genetic alteration that would explain the BCM phenotype in all assessed individuals.24 In one study the structure of the opsin array did not reveal the genetic mechanism for the disorder in 9 of 35 affected patients24 which may suggest genetic heterogeneity yet to be identified in BCM.

RGS9/R9AP retinopathy (bradyopsia)

Progressive retinal dystrophies

Rod–cone dystrophies

The rod–cone dystrophies (retinitis pigmentosa (RP)) are a clinically and genetically heterogeneous group of disorders with progressive loss of rod and later cone photoreceptor function leading to severe visual impairment. RP usually occurs as an isolated retinal abnormality, but it may also be seen with systemic abnormalities (see Chapter 45).

Leber’s congenital amaurosis

Clinical findings

Leber’s congenital amaurosis (LCA) is a severe congenital or early infant-onset non-syndromic retinal blindness described by Theodore Leber in 1869. He characterized the disorder by a searching nystagmus, abnormal pupil responses, minimal if any vision beyond infancy, and a normal fundus appearance initially, followed by the development of pigmentary changes. He later described a milder form of the same disease which has had several names, including early onset severe retinal dystrophy (EOSRD), severe early childhood onset retinal dystrophy (SECORD), and early onset retinitis pigmentosa. LCA/EOSRD is the most common inherited cause of severe visual impairment in children, accounting for 10–18% of children in institutions for the blind.

Severe visual impairment is from birth or the first few months of life with roving eye movements or nystagmus and poor pupillary light responses. Eye-poking, the “oculodigital” sign, is common (Fig. 44.7). Fundus examination may be normal but a variety of abnormal fundus appearances may be present such as disk pallor, vessel attenuation, or mild peripheral pigmentary retinopathy. There may also be disk drusen, optic disk edema or pseudopapilledema (Fig. 44.8), a flecked retina, maculopathy, or nummular pigmentation. Affected infants often have high hyperopia, or less commonly high myopia, suggesting some interference with emmetropization.

Although most patients have normal fundi in infancy, signs of a pigmentary retinopathy appear in later childhood with optic disk pallor and retinal arteriolar narrowing. Other late signs, which may be related to eye-poking, include enophthalmos, keratoconus, and cataract. Eventual vision is in the region of 3/60 to perception of light, with progression not observed in all cases.

Following the discovery of many disease-causing genes (below) it has sometimes been possible to identify characteristic associated phenotypes (Figs 44.9 to 44.12): RDH12-associated disease is characterized by bone spicule pigmentation and maculopathy (Fig. 44.9) and CRB1-associated disease has nummular pigmentation, maculopathy, relative preservation of para-arteriolar RPE, with retinal thickening and loss of lamination on optical coherence tomography (Figs 44.10 and 44.11).

Jun 4, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Inherited retinal disorders
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