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Cone/Cone-rod dystrophy: for professionals


Overview

Prevalence
Inheritance
  • Autosomal dominant
  • Autosomal recessive in majority of cases
  • X-linked recessive
Genes involved (OMIM No.)35 genes identified to date with the most common being:
  • GUCY2D (#600179) in autosomal dominant cases
  • ABCA4 (#601691) in autosomal recessive cases
  • RPGR (#312610) in X-linked recessive cases
Symptoms
  • Loss of cone-mediated vision initially (central and colour vision) which progressively decline over time
  • Photophobia
  • Subsequent nyctalopia and peripheral VF loss in cone-rod dystrophy patients
Signs
  • Reduced best corrected visual acuity (BCVA)
  • Dyschromatopsia
  • High myopia in X-linked RPGR cases
  • Range of macular abnormalities ranging from absent foveal reflex, RPE disturbances to bull’s eye lesions and geographic atrophy
  • May be accompanied by bone-spicule pigmentation and/or chorioretinal atrophy in the periphery
Systemic featuresSome examples include:
Key investigations
  • Full-field ERG: Significant reduction in cone responses with less severe reduction in rod responses for cone-rod dystrophies
  • OCT: detailed assessment of the central outer retinal layers, specifically the EZ which is usually disrupted in the initial stages of the disease
  • FAF: assess areas of RPE dysfunction and atrophy
  • Kinetic perimetry: central scotoma +/- peripheral scotoma
  • Assessment/screening by other specialists may be required if features suggestive of wider systemic involvement are present or based on genetic result
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcular
  • Correct refractive errors
  • Low vision aids
  • Tinted glasses/contact lens for photophobia
  • Healthy diet consisting of fresh fruit and green leafy vegetables
Systemic
  • Multidisciplinary approach
Therapies under research

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Clinical phenotype

Presenting features

Cone or cone-rod dystrophies encompasses a group of progressive inherited retinal dystrophies (IRDs) characterised by predominant impairment of cone-mediated vision. In cone-rod dystrophies, this is usually accompanied or followed by subsequent rod dysfunction manifesting as nyctalopia and peripheral visual field loss. Disease onset is usually within the first two decades of life and the main presenting features are:

  • Reduced visual acuity (VA) not corrected fully by glasses
  • Colour vision disturbance
  • Photophobia

35 genes have been identified currently that cause cone/cone-rod dystrophies and as a result, there is significant inter- and intrafamilial phenotypic variability in terms of age of onset, severity of visual dysfunction, disease progression and clinical findings. Generally, cone-rod dystrophies are more severe than cone dystrophies with an earlier mean age of disease onset and a faster rate of visual decline. The mean age of achieving legal blindness (BCVA 6/60 or worse) in cone-rod dystrophy and cone dystrophy are 23 and 48 years old respectively according to a longitudinal study.[3] Compared to retinitis pigmentosa (RP), patients with cone- and cone-rod dystrophies tend to suffer from severe visual loss at an earlier age but this is highly variable.[2,4]

Fundal appearance

Due to the significant genetic heterogeneity, the fundal features are highly variable as well but patients usually have symmetrical ocular findings. The macula is predominantly affected but there might be more widespread involvement in the periphery. The following features may be observed:

  • Macula: Blunted foveal reflex, RPE disturbances or bull’s eye lesion which progresses to macular atrophy over time
  • Retinal periphery: Flecks (ABCA4-retinopathies), bone-spicule pigmentation and chorioretinal atrophy
  • Optic disc: Appears normal or there may be subtle temporal disc pallor in the early stages; waxy disc pallor in more advanced stages[2]
  • Blood vessel attenuation

In the early stages of the disease, cone and cone-rod dystrophies may be difficult to distinguish from macular dystrophies based on fundoscopic appearance alone but they can be differentiated with electrophysiological studies. Although pattern electroretinogram (ERG) responses are reduced in both, full-field ERG tends to be relatively preserved in isolated macular dystrophies.

On the other hand, advanced cone-rod dystrophies may be difficult to distinguish from advanced RP based on fundoscopy and ERG findings. In such situation, the initial symptomology and sequence of events are usually the only way to differentiate both phenotypes, along with genetic testing to identify the causative gene.

Other associated ocular features

Apart from the retinal changes, patients may have the following ocular features which can lead to further visual deterioration:

  • High myopia (especially in RPGR-associated cases)[4]
  • Nystagmus

Associated extraocular features

Cone/cone-rod dystrophy is usually an isolated ocular finding. However, in minority of cases cone-rod dystrophies may be associated with other systemic abnormalities. Some examples include:

  • Alstrom syndrome
  • Bardet-Biedl syndrome
  • Spinocerebellar ataxia Type 7 (SCA7) — An autosomal dominant neurodegenerative disorder characterised by progressive cerebellar ataxia and visual loss.[6] Central visual disturbance usually precedes neurological features. The macula appears normal initially but progresses to RPE pigment disturbances and then to geographic atrophy over time.[7]

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Genetics

Pathogenic mutations in 35 genes have been identified so far that account for about 60% of cases.[10] The most common causative genes are:

  • ABCA4 (60% of autosomal recessive cases); biallelic null mutations are associated with cone-rod dystrophies
  • GUCY2D (35% of autosomal dominant cases)
  • RPGR (73% of x-linked cases); most pathogenic variants causing cone/cone-rod dystrophies are located at the 3’ end of the ORF15 exon

Many of the identified causative genes encode proteins involved in photoreceptor morphogenesis/development and the phototransduction cascade.[10]

General FunctionGenes
PhototransductionCNGA3, CNGB3, GUCA1A, GUCY2D, OPN1MW, OPN1LW, PDE6C, PDE6H
Photoreceptor morphogenesis/developmentAIPL1, ADAM9, CDHR1, CERKL, CRX, KCNV2, PROM1, PRPH2, RAX2, SEMA4A
Photoreceptor ciliary development and transportC21orf2, CEP78, POC1B, RAB28, RPGR, RPGRIP1
Neurotransmitter releaseCACNA1F, CACNA2D4, RIMS1, UNC119
Signalling pathwayPITPNM3, TTLL5
Visual cycleABCA4, RDH5
Ion transportCNNM4, KCNV2
Unknown function C8orf37

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

1) Electrophysiology

In the early stages, there is delayed implicit time in the cone-specific 30 Hz flicker response. This is then followed by a decrease in amplitude in both 30 Hz flicker and single photopic flash (a- and b-waves) responses, which gradually deteriorate over time. [10] The rod responses are decreased as well in cone-rod dystrophies but not to the extent of the cone responses. Both responses are eventually extinguished in advanced stages.

It is important to note that about one-third of patients diagnosed with cone dystrophies may actually be early cone-rod dystrophies as it can take up to 10 years for rod dysfunction to manifest on ERG. [3] In most cases, there is usually a decreased response in pattern ERG due to predominant macular involvement.

KCNV2-retinopathies display a characteristic ERG finding where abnormal cone responses are accompanied with “supranormal” rod responses. However, this is not associated with enhanced rod function. [11]

2) Fundus autofluorescence imaging (FAF)

FAF can reveal areas of RPE dysfunction and atrophy which may not be obvious on fundoscopy. The FAF findings are highly variable, where the abnormalities may be limited to the macula and/or involve the peripheral retina as well. [12]

Some FAF appearances may be characteristic of specific genotypes. For example, ABCA4-retinopathies tend to have areas of decreased AF centrally accompanied by a heterogeneous “speckled” background which may extend beyond the vascular arcades. There is usually peripapillary sparing of AF as well. [12]

The various fundal phenotypes of molecularly confirmed ABCA4-retinopathy. The patient in (A) has a central dark area of atrophy confined to the posterior pole. Flecks are seen up to the mid-periphery. Patient B has a larger confluent atrophic patch that is extending past the arcades. Flecks are noted up to the mid-periphery. Patient C has one large confluent atrophic patch with multiple smaller atrophic patches in the mid-periphery. As the disease progresses, the atrophic patches coalesce and extend to the periphery in a centrifugal direction (D). Note: peripapillary sparing in A and B and relative preservation of the far peripheral retina in all patients.

On the other hand, some cone-rod dystrophy patients harbouring RPGR mutations may have a progressively enlarging parafoveal ring of increased AF, which is associated with reduced rod and cone sensitivities. [13]

The retina of a patient with cone dystrophy due to mutation in the RPGR gene. The retina looks relatively normal apart from the macula which looks degenerated.
A hemizygous RPGR male with primarily cone dysfunction. Wide field colour fundus photograph (A) shows central macular atrophy with vessel attenuation. FAF imaging (B) shows the area of central macular atrophy clearly, delineated by an hyperautofluorescent ring. The periphery is relatively preserved.
The central hyperautofluorescent ring seen in the FAF image above represents the border between preserved and atrophic retina.

The advent of wide-field FAF has enabled clinicians to better predict generalised retinal function by measuring the area of abnormal AF. This has been shown to correlate well with visual fields and ERG findings. [14]

3) Optical coherence tomography (OCT)

The overall macular structure including the outer retinal layers and RPE integrity can be ascertained through OCT. Abnormalities of the outer retinal layers (disruption or loss), specifically the ellipsoid zone (EZ) and external limiting membrane (ELM) are frequently observed in the foveal or perifoveal regions. Over time, the foveal outer nuclear layer (ONL) undergoes thinning as well. Outer retinal layer disruption in the peripheral macula is more variable.

Some specific characteristics can be observed with certain genotypes. For instance, EZ disruptions are usually limited to the fovea in PDE6C and ABCA4-retinopathies tend to have hyper-reflective deposits above the RPE. [12]

Various retinal images of a patient with achromatopsia or cone dystrophy due to mutations in the PDE6C gene. The is a dark area in the centre of the retina, which demarcates the area of retinal degeneration.
Multimodal imaging of a patient with PDE6C-achromatopsia/cone dystrophy. Central macular atrophy can be appreciated clearly on FAF imaging (B), surrounded by a ring by hyperautofluorescence. OCT scan through the macula (C) shows foveal and parafoveal outer retinal and RPE atrophy, corresponding to the area of hypoautofluorescence. The outer retinal layers look relatively preserved beyond this area of hypoautofluorescence.
OCT scan of a patient with ABCA4-retinopathy showing a retinal fleck appearing as a hyper-reflective deposit above the RPE/Bruchs layer.

4) Kinetic perimetry

A central scotoma is usually present which may be accompanied with peripheral scotoma in cone-rod dystrophy cases.

Systemic

As cone/cone-rod dystrophies may be the first manifestation of syndromic cases, careful systemic enquiry during history taking and an increased awareness of potential extraocular involvement are crucial in identifying patients that may require input from other specialities. In children, consider early referral to paediatricians for a development assessment and screening for any systemic features.

Genetic testing can also flag up patients that may require systemic screening but clinical findings must be taken into context when interpreting the results as some genes are associated with both syndromic and non-syndromic cone-rod dystrophy (e.g. C8orf37).

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Diagnosis

Similar to RP, most cases tend to present with no family history (sporadic). Therefore, genetic testing should be undertaken to obtain a molecular diagnosis which can help facilitate genetic counselling, advice on prognosis and future family planning, direct further clinical management and aid in clinical trial participation.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing

Most sporadic patients are found to have autosomal recessive inheritance from genetic testing and further parental segregation of causal variants. [15]

Related links

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Management

Ocular

Supportive management:

  • Correcting any refractive errors
  • Referral to low vision services
  • Directing patients to supporting organisations
  • Tinted glasses/contact lens for photophobia
  • Encourage the use of assistive technology that may improve quality of life
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
  • Vitamin A supplementation should be avoided in those with ABCA4 mutations

Systemic

A multidisciplinary approach is required if a child is affected by syndromic cone-rod dystrophy such as Alström syndrome and Bardet-Biedl syndrome.

Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

Related links

Family management and counselling

Cone/cone-rod dystrophies can be inherited in the following Mendelian pattern:

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis. However, most patients tend to be simplex cases on presentation and thus may make counselling challenging prior to genetic testing.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in cone/cone-rod dystrophies

Much of the current research in cone/cone-rod dystrophies are focused on elucidating the remaining causative genes and their molecular mechanisms, understanding the natural history of the disease and establishing optimum clinical trial endpoints. Findings from ongoing research in ABCA4-retinoapthies could pave the way for the development of novel therapies for one of the most common causes of cone-rod dystrophies. Other studies that may play similar roles include:

Related links

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Further information and support

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References

  1.  Roosing S, Thiadens AA, Hoyng CB, Klaver CC, den Hollander AI, Cremers FP. Causes and consequences of inherited cone disorders. Prog Retin Eye Res. 2014;42:1-26
  2.  Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7
  3.  Thiadens AA, Phan TM, Zekveld-Vroon RC, et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012;119(4):819-826
  4.  Talib M, van Schooneveld MJ, Thiadens AA, et al. CLINICAL AND GENETIC CHARACTERISTICS OF MALE PATIENTS WITH RPGR-ASSOCIATED RETINAL DYSTROPHIES: A Long-Term Follow-up Study. Retina. 2019;39(6):1186-1199
  5.  Michaelides M, Holder GE, Bradshaw K, Hunt DM, Moore AT. Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene. Ophthalmology. 2005;112(9):1592-1598
  6.  Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ‘the Drew family of Walworth’. Brain. 1982;105(Pt 1):1-28
  7.  Aleman TS, Cideciyan AV, Volpe NJ, Stevanin G, Brice A, Jacobson SG. Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res. 2002;74(6):737-745
  8.  Jalili IK, Smith NJ. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet. 1988;25(11):738-740
  9.  Michaelides M, Bloch-Zupan A, Holder GE, Hunt DM, Moore AT. An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta. J Med Genet. 2004;41(6):468-473
  10.  Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M. Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy. Br J Ophthalmol. 2019;103(5):711-720
  11.  Stockman A, Henning GB, Michaelides M, et al. Cone dystrophy with “supernormal” rod ERG: psychophysical testing shows comparable rod and cone temporal sensitivity losses with no gain in rod function. Invest Ophthalmol Vis Sci. 2014;55(2):832-840
  12.  Boulanger-Scemama E, Mohand-Saïd S, El Shamieh S, et al. Phenotype Analysis of Retinal Dystrophies in Light of the Underlying Genetic Defects: Application to Cone and Cone-Rod Dystrophies. Int J Mol Sci. 2019;20(19)
  13.  Robson AG, Michaelides M, Luong VA, et al. Functional correlates of fundus autofluorescence abnormalities in patients with RPGR or RIMS1 mutations causing cone or cone rod dystrophy. Br J Ophthalmol. 2008;92(1):95-102
  14.  Oishi M, Oishi A, Ogino K, et al. Wide-Field Fundus Autofluorescence Abnormalities and Visual Function in Patients With Cone and Cone-Rod Dystrophies. Investigative Ophthalmology & Visual Science. 2014;55(6):3572-3577
  15.  Birtel J, Eisenberger T, Gliem M, et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018;8(1):4824

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Updated on January 18, 2021
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