Cone rod dystrophies

0 Address: Inserm U. 583, Physiopathologie et therapie des deficits sensoriels et moteurs, Institut des Neurosciences de Montpellier , BP 74103, 80 av. Augustin Fliche, 34091 Montpellier Cedex 05 , France Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness. - Disease name Cone rod dystrophies (CRDs) Definition and diagnosis criteria CRDs are inherited retinal dystrophies that belong to the pigmentary retinopathies group. Functional signs and symptoms  Decrease in the visual acuity is the earliest symptom  Photophobia also occurs early  Frequent dyschromatopsia  Night blindness occurs later  Patchy losses of peripheral vision follow  Pigmentary deposits resembling bone spicules, frequently in macular area  Attenuation of the retinal vessels  Waxy pallor of the optic disc  Various degrees of retinal atrophy Electroretinogram (ERG)  Implicit time (between a- and b-wave peaks) shift at the 30-Hz flicker responses, along with delayed a- and b-wave single flash photopic response are early signs before amplitude reduction  Dramatic decrease of amplitudes of both a- and b-waves  Predominant involvement of photopic (cones) over scotopic (rods) responses Clinical description Non syndromic cone rod dystrophies CRDs present first as a macular disease or as a diffuse retinopathy with predominance of the macular involvement. In contrast to the symptoms of the rod cone dystrophies (RCDs, typical retinitis pigmentosa) resulting from predominant rod involvement, i.e. night blindness and loss of peripheral vision, the clinical signs of CRDs reflect the predominant involvement of cones, which leads to decreased visual acuity and loss of sensitivity in the central visual field. This fits the original description of the CRD entity in which cone loss precedes rod degeneration. However, in some cases, diffuse retinopathy affects simultaneously cones and rods, resulting in both night blindness and loss of visual acuity. These cases may also be considered as CRDs, although they overlap with other entities (see differential diagnosis). In general, CRDs are more severe than RCDs because the loss of patients' autonomy occurs earlier. It is convenient to describe two stages in the disease course of CRD. In the first stage, the main symptom is decreased visual acuity, which is usually discovered at school, in the first decade of life, and which does not significantly improve with spectacles. Patients often have a noticeable deviated gaze to project images on parafoveal regions of their retina that are less damaged. Along with this symptom, there are intense photophobia and a variable degree of dyschromatopsia. In contrast, night blindness is not mentioned by patients or, when present, is never as prominent as the decrease in visual acuity. Visual field testing shows central scotomas, while periphery is spared. As a result, patients have no difficulties to move. Fundus examination shows pigment deposits and various degrees of retinal atrophy in the macular region (Figure 1). Retinal vessels are usually normal or moderately attenuated. The optic disc is often pale at early stages, particularly on the temporal side, which accounts for the macular fibre bundle. At this stage, the question is to differentiate CRDs from macular dystrophies such as Stargardt disease, cone dystrophies and other rare macular conditions. Additional investigations help the diagnosis. First, fluorescein angiography and fundus autofluorescence show that the peripheral retina is also involved with heterogeneity in the fluorescence, but to a lesser extent than the macula. Second, the electroretinogram (ERG) shows a shift in implicit time of cone responses, followed by a decrease in both cone and rod responses. Cone responses are more severely affected than rod responses. In the second stage, night blindness becomes more apparent and the loss in the peripheral visual field progresses. Therefore, patients have difficulties to move autonomously. In addition, visual acuity continues to decrease to a level where reading is no longer possible. rFFeuiggnaudturinesgo1wfiath45a yloesasr--oofl-dfupnacttieionnt mwiutthatcione(Ero10d8d7yXst)rionpAhByCsAe4gFundus of a 45 year-old patient with cone rod dystrophy segregating with a loss-of-function mutation (E1087X) in ABCA4. Note the presence of various-shaped pigment deposits in the posterior pole with atrophy of the retina, while the retina appears less damaged in periphery (upper part of the photograph). Nystagmus is often present. At this stage, patients are legally blind (visual acuity <1/20), even though large parts of the peripheral visual field remain preserved. Syndromic cone rod dystrophies There are a few syndromes in which retinal degeneration characteristically feature (...truncated)