The cone dystroph ies M.P. SIMUNOVIC, A.T. MOORE Summary dystrophy with advancing age. All forms of cone dystrophy result in reduced visual acuity The cone dystrophies are a heterogeneous and colour vision deficiency together with group of inherited disorders that result in psychophysical and electrophysiological dysfunction of the cone photoreceptors and evidence of abnormal cone function.2 In this sometimes their post-receptoral pathways. The paper we aim to review current knowledge major clinical features of cone dystrophy are about the diverse group of disorders that photophobia, reduced visual acuity and comprise the cone dystrophies. abnormal colour vision. Ganzfeld electroretinography shows reduced or absent cone responses. On the basis of their natural The stationary cone dystrophies history, the cone dystrophies may be broadly divided into two groups: stationary and The stationary cone dystrophies may be progressive cone dystrophies. The stationary effectively subclassified on the basis of cone dystrophies have received more psychological testing. The major forms of attention, and subsequently our knowledge of stationary cone dystrophy are: anomalous their molecular genetic, psychophysical and trichromacy, dichromacy, monochromacy and clinical characteristics is better developed. oligocone trichromacy. Although the Various methods of classification have been congenitally colour deficient possess a cone proposed for the progressive cone dystrophies, population that is deviant from the normal, but none is entirely satisfactory, largely their visual dysfunction is confined to colour because the underlying disease mechanisms vision. A full discussion of the congenital colour are poorly understood. Multidisciplinary vision deficiencies will not be developed, and studies involving clinical assessment, we would direct the reader to several reviews molecular genetics, electrophysiology and published on the subject.3-6 psychophysics should lead to an improved understanding of the pathogenesis of these Monochromatism disorders. By definition, the monochromat requires only Key words Cone, Dystrophy, Photoreceptor, Rod one primary in order to match the entire visible spectrum. As we will see, many of those who There are a large number of different inherited are labelled as 'monochromats' do display a disorders that give rise to cone dysfunction. crude form of residual colour discrimination Usually, the genetic mutations result in when tested under specific conditions. This has functional abnormalities that are confined to the two unfortunate consequences. The first is that eye, but there are a number of rare disorders in it gives rise to misnomers such as 'incomplete which the retinal dystrophy is associated with achromatopsia'. The second is that, because systemic abnormalities. St Albertus Magnus has there is no recognised standard for assessing been credited with the first description of cone such subjects, two independent laboratories dystrophy; this account dates from the using different testing apparatus may differ in MP. Simunovic the diagnosis of identical conditions. thirteenth century.l Cone dystrophy may be Department of Experimental Monochromats may be subdivided according to inherited as an autosomal recessive, autosomal Psychology dominant or X-linked recessive trait. There is the type of photoreceptor(s) they retain. The University of Cambridge considerable genetic heterogeneity, even within distinction between some forms of Cambridge, UK these genetic subtypes. The stationary cone monochromatism is unclear, and clarification A.T. Moore � Ophthalmology Department dystrophies are congenital, in that the cone will have to await the discovery of the Addenbrooke's Hospital dysfunction is thought to be present at birth underlying genetic mutations. Hills Road (rod photoreceptor function is normal). The Cambridge CB2 2QQ, UK progressive cone dystrophies usually present in Rod monochromatism Tel +44 (0)1223 216700 childhood or early adult life, and patients often Fax +44 (0) 1223 240085 develop rod photoreceptor dysfunction in later Rod monochromatism is also known as '!TO e-mall:[email protected] life. There is, therefore, considerable overlap monochromacy and 'complete' or 'typical' A.T. Moore between the cone and cone-rod dystrophies: the achromatopsia, and is inherited in an autosomal Moorfields Eye Hospital majority of patients with progressive cone recessive fashion. Patients with this condition City Road dystrophy develop a generalised retinal appear to display rod vision only. As a result, London, UK Eye (1998) 12, 553-565 Ii) 1998 Royal College of Ophthalmologists 553 Fig. 1. Fundus photographs of a girl aged 11 years with rod monochromatism showing blunted foveal reflex. the rod monochromat can detect only brightness of the rod monochromat is unremarkable, except that differences, and is therefore truly colour-blind? Patients there may sometimes be a blunted foveal reflex (Fig. 1). with this disorder usually present in early infancy with Krill et al.9 have emphasised that if there is macular nystagmus, marked photophobia and reduced acuity. atrophy present it is likely that the patient has a The nystagmus is typically of rapid frequency and low progressive cone dystrophy. amplitude. In many cases, the nystagmus decreases in Electroretinography reveals that cone responses are severity by the end of the first decade. Commonly, there absent, though rod responses are normal2,l0 (Fig. 2). Rod is a high hypermetropic refractive error. In affected monochromats fail to recognise any plates on the individuals who are old enough for accurate assessment, common 'plate' tests (such as the Ishihara and HRRtests) the visual acuity is usually about 6/60 when assessed and make characteristic D-15 ordering patterns, with the using a standard letter chart at photopic illumination 'apparent axis' of confusion lying halfway between those levels. A central scotoma may be demonstrated with of a tritan and a deutan. Although there is no true colour formal perimetry, although this type of scotoma cannot perception, patients may be able to distinguish some be demonstrated in all patients.8 The fundus appearance colours via their relative lightness. CONE + + L.:0).lV L20llV 30Hz Flicker _ 10 ms _ 10ms D.A. Red Flash ROD S.F. S.F. -1Log Blue Blue + 1 Log L:S).lV ms t 10 Stim Stim Fig. 2. The e/ectroretinograms of a normal control subject (left) and a rod monochromat aged 11 years (right! using gold foil recording electrodes. The rod responses are normal, but there are no recordable cone responses. 554 Histopathological investigation of donor eyes from there are at least four forms of achromatopsia of subjects with rod monochromatism has demonstrated autosomal recessive inheritance. In type I, there is no the presence of cone-like structures in the retinaY-14 evidence of cone function (these patients are rod However, the studies have given conflicting reports as to monochromats), in type II incomplete achromatopsia, the nature and distribution of these cones. Larsenll colour matches are governed by rods and M-cones, in found thatthe cones had short outer segments with large type III incomplete achromatopsia, colour matches are diameters, especially around the macular area. Harrison mediated by the L- and M-cones, and in the final form, and colleagues12 reported that the cones were type IV, colour matches are mediated by rods, L-cones abnormally shaped and reduced in number throughout and S-cones. It appears that type II incomplete theentire retina. Falls and colleagues13 found cone achromatopsia corresponds to 'incomplete , numbers at the fovea to be normal, but their shape to be achromatopsia with protan luminosity ?8 It also appears abnormal.In theperiphery the cones were scarce, though that type IV incomplete achromatopsia corresponds to , less commonly malformed. In contrast Glickstein and 'incomplete achromatopsia with deutan luminosity ?9,30 Heath14found that the fovea was totally devoid of cones; Because there are several reports of pedigrees in which those present in the surrounding area were abnormal in both rod monochromacy and incomplete achromatopsia morphology. occur,26,27,31,32 it is likely that rod monochromatism and Psychophysical testing may also reveal residual cone some forms of incomplete achromatopsia, such as type function in rod monochromats. For example, a II,27 may represent phenotypical variations of a single Stiles-Crawford effect may be demonstrated,15 and the genetic defect. dark adaptation curve may be biphasic.15-19 Increment threshold experiments may also show a duplex function?0,21 In an extensive survey of the Blue cone monochromatism psychophysical literature, Sharpe and Nordby8 report The blue cone monochromat possesses a normal rod that 18 out of a total of 37 investigations of rod monochromatism claim to have found psychophysical system with a normal S-cone mechanism. Blue cone evidence of cone function. In addition, Krastel and monochromatism is an X-linked recessive disorder, and (6/24-6/60), Jaege?2 have demonstrated, using large fields, that many affected males present with reduced acuity of those labelled as rod monochromats may have nystagmus and photophobia? The condition is also residual cone function. However, many of the studies sometimes known as X-linked atypical achromatopsia or 'TTl should be treated with caution: it is possible that the monochromacy. Most affected individuals are myopic; investigators were describing occult cases of incomplete fundus examination may show tilted