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Do you know what rare diseases are related to vision?

13/12/2019 · خبر
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Rare diseases are minority, but numerous: there are approximately 7,000 diseases. Some of them are related to vision. To coincide with La Marató de TV3 telethon broadcast which this year is devoted to rare diseases, the Institut de la Màcula has prepared an awareness-raising campaign to publicise all these pathologies

Rare diseases (also called minority or orphan) are defined as those that affect one in 2,000 people. As a whole, there are around 7,000 rare diseases worldwide, with many lacking a treatment. Research is the only strategy to develop therapies for sufferers.

Some of these pathologies are related to vision and, coinciding with La Marató de TV3 telethon, which this year is dedicated to rare diseases, the Institut de la Màcula has started an awareness-raising campaign to publicise the ocular ones: Stargardt's disease, retinitis pigmentosa, choroideraemia, Leber's congenital amaurosis, X-linked retinoschisis, Gyrate atrophy, fundus albipuntactus, Best vitelliform macular dystrophy, Usher syndrome and cone dystrophy are some examples.

Below, you will find further information about each of these:

Stargardt’s disease

Stargardt's disease (OMIM 248200) is the most frequent macular dystrophy. Most cases are inherited in an autosomal recessive manner. The decrease in vision caused by this disease usually affects young people, with an impact especially on adolescents and young adults of under 20 years old (1:10,000). Stargardt's disease and fundus flavimaculatus are two clinical presentations of the same disease. At the histological level, a cluster of lipofuscin-like material is produced in the retinal pigment epithelial cells for the ABCA4 gene mutation. This mutation is transmitted when both parents suffer from the malformation of this gene.

Stargardt's disease causes unfocused vision lacking in sharpness. This makes it hard to recognise faces and shapes, to read both near and far, and finally to confuse colours with similar tones (for example, black and navy blue). Stargardt’s also causes difficulty when adapting to dim light. Although it does not produce absolute blindness, sufferers may lose visual acuity until they reach legal blindness.

At present, there is no treatment for this pathology although research in this field continues to be highly active. Centres in Europe and the United States participate in a variety of clinical trials with the aim of finding an effective therapy for Stargardt patients. This research embraces a pharmacological approach as well as gene and stem cell therapies.

The main pharmacological treatments are divided into two large groups: visual cycle modulators and complement inhibitors. The Institut de la Màcula, in close collaboration with the Barcelona Macula Foundation (BMF), is the only centre in Spain to be participating in the clinical trial that aims to test the efficacy and safety of Zimura® (IVERIC bio; multi-centre phase 2b study: OPH2005) in Stargardt patients.

Retinitis pigmentosa

Retinitis pigmentosa (RP) is an inherited degenerative eye disease that severely reduces visual capacity, often to blindness. With a prevalence of 1:4000, sufferers in Spain number over 15,000. It is estimated that 60,000 people are carriers of the defective genes responsible for the disease and, therefore, possible transmitters. The onset of the disease generally affects young people and the initial symptoms are dark adaptation difficulty and a progressive loss of the visual field.

Retinitis pigmentosa describes a group of inherited retinal diseases that are characterised by a progressive loss of photoreceptors (apoptosis), especially those of a rod type, and of the pigment epithelium of the retina due to mutations of its proteins and specific enzymes. The hereditary component appears in half the number of retinitis pigmentosa cases and the prognosis, as well as its progression, may be related to this.

There is no effective treatment to combat retinitis pigmentosa. The identification of the gene responsible for the disease is a key aspect of the clinical management of the RP patient by gene therapy. This not only means we can confirm the diagnosis, but also establish the genotype/phenotype correlation, offer a more accurate prognosis and, in the near future, indicate one type of treatment or another.

Researchers from the Barcelona Macula Foundation (BMF) have started the DRUG4SIGHT project funded by La Caixa with the Institute for Bioengineering of Catalonia (IBEC) and other state-level entities to develop new drugs in patients with retinal degeneration. The paradigm of this project varies completely from other therapeutic approaches. Here, the intention is to discover and characterise a series of drugs that can stimulate proteins still present in the degenerated retina and make the non-degenerated remnant cells act as photoreceptors, light-sensitive cells. The preliminary results are encouraging but need to be confirmed in animal models with a visual system more akin to that of a human being.


Choroideraemia (OMIM 300390) is a recessive disease caused by mutations to the CHM gene, located on chromosome Xq21.2. The mutation causes the lack of a protein, Rab escort protein 1 (REP1), which is thought to be involved in intracellular traffic and/or rod function. It typically affects men (1:50,000), while women are carriers.

The disease causes a loss of the choriocapillaris (the layer of more intense capillaries of the choroids), the retinal pigment epithelium and the photoreceptors (mainly the rods). It begins in the mid-periphery and progresses centripetally towards the macula, with characteristically well-defined margins between the affected and healthy retina. Symptoms usually first appear in young people. Patients notice a loss of visual field and worsening of night vision that progress towards central vision reduction similar to that observed in patients with retinitis pigmentosa.

Although it lacks a treatment, choroideraemia is one of the inherited diseases for which there are the most registered interventional studies (15 at, viewed December 3, 2019). It is a monogenic disease caused by alterations in a single gene. Therefore, treatment by gene therapy, in which the affected gene is replaced by one that functions normally, is being tested with encouraging results. The trials taking place in many countries include the STAR study, a phase III clinical trial conducted in the U.S. and Europe.

Leber's congenital amaurosis

Leber’s congenital amaurosis (LCA) is a disease, usually autosomal recessive, that is present at birth or shortly afterwards. Many mutations in different genes have been described as responsible for its development. Estimated to have a prevalence of 1:40,000, it can be associated with other systemic disorders (developmental delay, renal dysfunction etc.).

LCA is characterised by retinal degeneration, in which a seemingly normal fundus progresses towards generalised pigment abnormalities, vascular attenuation and atrophy of the retina and optic nerve. Vision is severely affected, and newborns may display nystagmus (oscillatory eye movement), photophobia (abnormal sensitivity to light) or strabismus (poor alignment of the visual axes).

The disease cannot be treated in most cases, although some associated conditions can be addressed (high hypermetropia, cataract etc.). However, 10% of LCA cases are due to mutations in the RPE65 gene (LCA type 2, OMIM 180069). Here, we can use Luxturna® (voretigene neparvovec by Spark Therapeutics), a gene therapy based on the replacement of the defective gene by a functional gene that showed good visual results. In January 2018, it obtained approval from the FDA (the US Food and Drug Administration), and in April 2019 from the AEMPS (Spanish Agency of Medicines and Medical Devices). This marked a milestone as it was the first gene therapy in ophthalmology to be approved by a regulatory agency.

X-linked retinoschisis

X-linked retinoschisis (OMIM 312700) is a bilateral ocular disorder that appears during childhood, caused by mutations in the RS1 gene located on chromosome Xp22.13. As its name implies, transmission of the condition is linked to the X chromosome. It affects only men (1/ 5,000-1/25,000) although women are carriers and have a 50% chance of transmitting the mutation to their children.

The mutated gene in X-linked retinoschisis (RS1) encodes for retinoschisin, an adhesive protein that participates in the structural and functional integrity of the retina. Thus, the fundus is characterised by the presence of cysts in the foveal area of the retina and by radial striations. Sufferers display central vision reduction and reading difficulties. The loss stabilises during youth to decrease again by the age of 50-60.

Although there is no approved treatment for the disease, there are currently two active clinical trials ( viewed December 3, 2019) to assess the safety, tolerability and efficacy of a gene therapy treatment.

Some of the complications secondary to this disease are retinal detachment (5-22%) and vitreous haemorrhage (4-40%). This is why, despite the current lack of a treatment, periodic checks are recommended to prevent or immediately treat any complications.

Gyrate atrophy

Gyrate atrophy (OMIM 258870) is a rare disease caused by mutations in the gene that encodes ornithine aminotransferase, OAT, (10q26). Under-activity of this enzyme produces hyperornithinaemia, but the mechanism by which it leads to chorioretinal atrophy remains unknown. It is of autosomal recessive inheritance and its prevalence is unknown (estimated as 1/50,000). The onset age varies (1 month-44 years).

The initial symptoms are night blindness and visual field reduction caused by multiple circular areas of chorioretinal atrophy in the periphery. Over the years, the atrophic areas grow, converging towards the macula and resulting in a loss of central vision. Patients may present associated symptoms such as myopia with marked astigmatism, early-onset posterior subcapsular cataract and cystic macular oedema.

It has been described in various studies that an arginine-restricted diet (ornithine precursor) or a low-protein diet may reduce the serum level of ornithine, thereby delaying the progression of chorioretinal atrophy and visual loss. For this reason, it is particularly important to keep this in mind, since dietary intervention can delay progression of the disease. Although some clinical trials have been conducted with gene therapy, none are currently active ( viewed December 3, 2019).

Fundus Albipuntactus

Fundus albipuntactus (OMIM: 136880) is a retinal dystrophy that first appears in childhood. This pathology is hereditary; it can be autosomal dominant or recessive and its prevalence is unknown. The autosomal dominant form is caused by a mutation in the PRPH2 gene and the recessive form is associated with a mutation in the RDH5 gene.

The RDH5 gene is involved in the visual cycle. This gene is responsible for providing instructions to the enzyme 11-cis retinol dehydrogenase 5, which plays an important role in the encoding of light in electrical signals. Therefore, mutations in this gene will cause a deficit in the function performed by 11-cis retinol dehydrogenase 5, altering the visual cycle and consequently vision, especially in dim light.

At the ocular level, fundus albipuntactus is characterised by the appearance of numerous small, rounded and white-yellowish retinal lesions that are distributed mainly in the mid-periphery, without macular impact.

Patients affected by this disease have non-progressive night blindness (with prolonged light to dark adaptation times) so it is important to distinguish them from other progressive entities with similar symptoms such as retinitis pigmentosa. Vision in normal lighting conditions is unaffected.

At present, a study is being conducted in the United States that registers patients with inherited degenerative retinal diseases on a database. The creation of these databases will provide greater knowledge of the disease and its natural history, as well as data about its prevalence.

Best vitelliform macular dystrophy

Best vitelliform macular dystrophy (BVMD) (OMIM 153700) is a disease that first appears in childhood and adolescence. Showing a prevalence of 1 to 9 cases in every 100,000, it affects more men than women (3:1) and is autosomal dominant inherited.

In most cases, BVMD is caused by a mutation in the BEST1 gene (located on chromosome 11q12). This gene is responsible for encoding bestrophin-1, a chlorine channel that is expressed in retinal pigment epithelium (RPE), so an alteration in this protein produces the accumulation of lipofuscin as a result of an abnormal ion exchange.

BVMD is characterised by a yellowish macular lesion in the form of an “egg yolk”, due to the abnormal lipofuscin accumulation between the photoreceptors and the RPE. In more advanced stages, there is atrophy of the RPE. Patients generally suffer central visual acuity reduction, metamorphopsia, protanopia and an alteration of the Arden index in the electrooculogram. However, peripheral vision and darkness adaptation are normal.

Over time, BVMD can evolve into geographic atrophy. One of the associated complications is the appearance of a subfoveal choroidal neovascular membrane (CNV), although this does not usually occur in children.

The treatments being carried out in BVMD patients are aimed at the possible complications stemming from the disease, such as the use of anti-VEFG in the case of CNV appearance. Studies conducted in recent years have identified the different autofluorescence patterns (FAF) present in this pathology. Therefore, it is important to monitor BVMD in the long term since the clinical modifications in the FAF will improve knowledge about the disease and its prognosis according to the pattern. In addition, different studies are being conducted in the United States, including those with gene therapy and stem cells.

Usher Syndrome

Usher syndrome (US) is an inherited autosomal recessive disease characterised by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa (RP) and progressive vision loss. Onset is usually during childhood and it has a prevalence of 1-9: 100,000 (and in the European population of 3-4: 100,000).

Three types of US have been identified, based on differences in auditory and vestibular function (retinitis pigmentosa is common in all three types): (a) type 1, in which hearing loss is congenital, profound and there is no vestibular function; retinitis pigmentosa does not manifest itself at birth and the mutations involve five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) and a locus (USH1E); (b) type 2, with less severe congenital deafness with preserved vestibular function, and mutations in the USH2A, GPR98 and DFNB31 genes and possible locus (15q); and (c) type 3, with later onset of both deafness and retinitis pigmentosa, with mutations in CLRN1.

Despite much research, the syndrome currently lacks treatment. Research focuses on the development of gene therapies through subretinal injections, intraocular implants of neuroprotective agents or so-called "bionic eyes." The need to work with a multidisciplinary team that also includes otolaryngologists, speech therapists and psychologists should be taken into account. Cochlear implants can help maintain auditory remains.

Cone dystrophy

Cones dystrophy (OMIM 602093) is a group of inherited retinal diseases with an autosomal recessive or dominant pattern. It usually occurs in childhood or in the early years of adulthood and its prevalence is unknown, while in cone-rod dystrophy, it is estimated to be around 1:40,000 people.

The characteristic symptoms are the progressive visual acuity and colour vision loss as well as photophobia (abnormal sensitivity to light). In the electroretinogram (ERG), only the cones are affected, with rod preservation. In some cases, termed cone-rod dystrophy, the rods may also be affected in the advanced stages; in these cases, the ERG also shows rod impact. In ophthalmoscopic terms, these dystrophies are characterised by the presence of pigment deposits in the macular region, which can take on a "bull's eye" appearance.

Cone dystrophy and rod-cone dystrophy have been associated with mutations in the GUCA1A gene and chromosomes 6q, 17p and 19q. Other diseases in which there is a selective impact on cones include achromatopsia or enhanced S-cone syndrome. Mild colour vision alterations are entities that are distinct from cone dystrophy.

There is currently no treatment that slows the evolution of this condition and restores vision. However, there are strategies aimed at helping patients to cope with the social and psychological impact of visual loss. Low vision aids (magnification systems, filters) can improve patient quality of life.


  • Yannuzi, L. A. (2016) The retina atlas. Elsevier
  • Agarwal, A (2011) Gass’ Atlas of macular diseases. Elsevier
  • Online Mendelian Inheritance in Man (2019). Available at
  • Clinical Trials (2019). Available at http:///
  • El portal sobre enfermedades rares y medicamentós huérfanos (2019). Available at

Authors: Clara Abadías, Marc Biarnés, Miriam Garcia and Cristina Romero

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Last modified: 23 June, 2022 - 9:47

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