Clinical diagnosis is based on the early decrease of visual acuity and photophobia, lesions in fundus, hypovolted ERG traces with predominant cone involvement, and progressive worsening of these signs. Full field ERG is the key test, particularly when patients are asymptomatic and show normal fundus at early stages. It is important to ascertain the diagnosis by repeating the examination one or two years after it has been first established. Multifocal ERG could be useful to follow precisely the functionality of the central retina.
At present, a systematic molecular testing is not routinely performed, due to the tremendous genetic heterogeneity of the disease. However, rapid and large-scale mutation screening techniques are developing and several laboratories perform search for mutations in the most frequently involved genes, including ABCA4
; strategies to test in a short time several dozen of genes for a single patient DNA are emerging [23
In some instances, molecular diagnosis for certain genes is performed by the laboratories that have discovered them.
Differential diagnosis of non syndromic CRDs with other pigmentary retinopathies
CRDs are usually clearly differentiated from primary peripheral retinopathies and macular dystrophies. However, CRD may sometimes share features with several clinical entities.
• Typical RP (rod cone dystrophy, RCD). In typical RCD, the diagnosis is easy because the first symptom is night blindness. This symptom typically remains isolated for several years with normal visual acuity before vision loss in daylight becomes prominent. In the fundus, pigment deposits are located in the periphery.
• RP with early macular involvement. In some cases, RCD has a typical slow progression but macular involvement occurs quite early, with some loss of visual acuity. A disease history characterized by predominant night blindness and prominent rod involvement on ERG supports the diagnosis of RCD.
• Early onset RP or late stage RP. In cases associated with early onset and severe RCD, the decrease in visual acuity with macular involvement may also occur early. It is again important to determine which sign, either night blindness or loss in central vision, appeared first in the disease course, and to perform ERG. The diagnosis may be particularly difficult when patients are examined at late stage. At that time, the typical changes in ERG are undetectable.
Leber congenital amaurosis (LCA)
This disease is associated with a high degree of visual impairment, which is already present at birth, and appears either as a rod- or cone-predominant disease, or both. Nystagmus, poor light fixation and reactivity, visual acuity lower than 1/20 and flat ERG are cardinal signs of the disease. Differential diagnosis with early onset CRD may be difficult because both diseases share the same clinical signs. The presence of a lapse time of several years before dramatic worsening of the visual disability will allow to classify the disease as CRD rather than LCA.
Large, extended maculopathies may be difficult to differentiate from end stage CRD or RP. In all cases, the full field ERG is a key investigation.
• Stargardt disease is a maculopathy in which peripheral retina usually remains free of lesions. The disease is easy to recognize with the presence of yellow flecks that may cover the entire fundus (fundus flavimaculatus), hyperfluorescent macular lesions (bull's eye) and dark choroid on the fluorescein angiography. However, there are extended lesions in some late stage Stargardt cases, and in addition, a number of CRD are caused by the "Stargardt gene", ABCA4. In these cases, the early stage of the CRD may be similar to Stargardt disease, but, in a decade, signs of peripheral involvement occur.
• Cone dystrophies. Rods remain normal in these diseases. Main clinical signs are loss of visual acuity, photophobia, dyschromatopsia, and exclusive cone involvement at ERG. However, in some cone dystrophies, there may be some rod involvement, particularly in late stage. In contrast to CRDs, rods remain at least partly spared at these late stages, whereas they are non recordable in late stage CRD. Another sign is the absence of macular lesions for many years, even though the visual acuity is decreased.
Stationary retinal diseases
This is essentially achromatopsia, which is diagnosed on the basis of mainly cone involvement (rod being not entirely normal), the lack of disease evolution, and the normal fundus.
Once the diagnosis CRD is made, patients should be informed and familial surveys recommended. Genetic counseling is always advised since all genetic forms can be encountered in CRD. A precise phenotypic diagnosis is always mandatory and is particularly useful in the absence of familial history or in sporadic cases.
Prenatal diagnosis can be performed in families in which the responsible gene has been identified. However, prenatal diagnosis (amniocentesis or chorionic biopsy) raises an ethical issue: whether the investigative risks associated with these invasive prenatal procedures are justified in a non life-threatening disease is questionable.
Management including treatment
Currently, there is no therapy that stops the evolution of pigmentary retinopathies or restores the vision. However, there are several therapeutic strategies aimed at slowing down the degenerating process (light protection, vitaminotherapy), treating the complications such as cataract, macular edema, inflammation, and helping patients to cope with the social and psychological impact of blindness. In fact, management of CRDs is not different from the management of typical RP. A particular emphasis should be put on filtrating spectacles to minimize photophobia and on low vision aid. Patients are often severely visually disabled or legally blind by the end of the second decade of life. Therefore, it is important that their education focuses on an adapted professional occupation (teaching, computer based activities, physiotherapist).
Cloned genes account for only a small part of the autosomal dominant CRDs cases and probably for half of the autosomal recessive cases. Therefore, genes remain to be discovered. Understanding the role of the encoded proteins often requires many years. Today, for a number of proteins, substantial information about their function is available, while some of the proteins remain poorly known.
A challenging issue is the elucidation of the precise steps leading from a gene mutation to photoreceptor degeneration. Data from animal models and clinical studies suggest that photoreceptors die by apoptosis at a linear rate throughout life (named the "one-hit hypothesis"), implying that they have a given probability to undergo apoptosis that remains constant from early to late stages of the disease . For certain genes or severe mutations, this probability will be high, while for others it will be lower. The results of experimental and clinical studies clearly indicate that the mechanisms of photoreceptor degeneration are multiple. In all genetic forms of CRDs studied until now, data are incomplete. In addition, it is likely that several apoptotic pathways are involved in the photoreceptor loss, sometimes concurrently, and this also needs to be carefully investigated. This knowledge is crucial to design therapies. The efficacy of various potential treatments has to be proven in animal models and in humans. For example, gene replacement therapy for RDS in mouse improves photoreceptor ultrastructure, but there is no significant effect on photoreceptor cell loss .