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Leber congenital amaurosis

This is part of Rare diseases.

Diagnosis: Leber congenital amaurosis

Synonyms: LCA, Early-onset retinitis pigmentosa

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Date of publication: 2013-12-27
Version: 2.0

ICD 10 code

H35.5

The disease

Leber congential amaurosis is the name of a group of congenital diseases of the retina affecting the rods and cones of the eye. As a result, vision is impaired or absent (amaurosis) from birth onwards. Early-onset retinitis pigmentosa is another name for this group of diseases, all of which give symptoms from a very young age.

Leber congential amaurosis is named after the German opthamologist Theodor von Leber, who described the disease in 1869. This disease is not to be confused with another eye condition described by Leber, Leber hereditary optic neuropathy. (A separate description, in Swedish only, can be found in the database of the Information Centre for Rare Diseases, on the website of The Swedish National Board of Health and Welfare.)

Occurrence

Leber congenital amuarosis occurs in between two and four children per 100,000 live births. In Sweden there are slightly more than 200 people with the disease.

Cause

Currently (2013), eighteen separate genetic mutations have been identified as causing Leber congential amaurosis.

Gene                Sub-group       Gene localisation
GUCY2D LCA1 17p13.1
RPE65 LCA2 1p31
SPATA7 LCA3 14q31.3
AIPL1 LCA4 17p13
LCA5 LCA5 6q14.1
RPGRIP1 LCA6 14q11.2
CRX LCA7 19q13.33
CRB1 LCA8 1q31.3
MNAT1 LCA9 1p36
CEP290 LCA10 12q21.3
IMPDH1 LCA11 7q32.1
RD3 LCA12 1q32.3
RDH12 LCA13 14q23.3
LRAT LCA14 4q31
TULP1 LCA15 6p21.31
KCNJ13 LCA16 2q37.1
IQCB1 3q21.1
MERTK 2q13

Table of mutations associated with Leber congenital amaurosis.

Of these, mutations in the AIPL1, CEP290, GUCY2D, RPE65, LRAT, RPBRIP1, IMPDH1 and CRB1 genes have been identified in Swedish families. In Sweden, it is estimated that approximately 40 per cent of all children diagnosed with Leber congenital amaurosis have a mutation in one of these genes. The functions of the proteins, whose production is controlled (coded for) by the 18 genes, are being successively identified. Most of the proteins form part of the primary (or immotile) cilia (microscopic, hair-like structures that extend from the surface of cells) and are important for the development and function of the photoreceptors of the retina; other proteins are associated with the eye’s retinal pigment.

Diseases affecting the primary cilia are termed ciliopathies. Cilia are present in almost all the cells of the body and are of importance as they have sensory, transport and other important functions, including cellular signal transduction. Other ciliary diseases include Alström syndrome, Bardet-Biedl syndrome and primary ciliary dyskinesia. These disorders are separately described in the Rare Disease Database of the Swedish National Board of Health and Welfare.

Heredity

The inheritance pattern of most forms of Leber congenital amaurosis is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

In a few, isolated, cases of the disease the inheritance pattern is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Symptoms

The disease is characterised by very restricted or absent vision from birth. The degree of severity of the condition depends on which gene is affected. Parents may notice that the baby does not fix his/her gaze, make eye contact or react to visual stimuli. The progression of the disease varies between children. Nystagmus (involuntary, rhythmical, repeated eye movements) is a sign that there is a residual degree of vision, and from around the age of six months the child can sometimes learn to use those parts of the retina which function best. Nystagmus may then diminish and the child can often fix his/her gaze and may also detect objects in the central field of vision. However, the child lacks both night vision and peripheral vision and is often sensitive to strong light. Changes in the retina are not visible in a newborn, but become apparent after one or two years.

Children with the form of the disease in which vision is absent may, from the age of three or four months, start to press their hands against their eyes. The reason for this is not yet understood. From the age of three to five months erratic and undulating eye movements can develop. The child often continues to press the eyes with fingers, wrist or the whole hand.

Those children with Leber congenital amaurosis who develop sight often experience a slow improvement during their first one to two years. Despite this, children often have a total absence of night vision, which in younger children may result in fear of the dark. Leaving a night light on can help. As the children’s field of vision is restricted, their overall vision is limited and they may have difficulties orienting themselves. For example, a child may be able to pick up small objects the size of a pea from the floor, but does not see that his or her parents have entered the room. In some children, this can lead to feelings of insecurity. Sensitivity to bright lights is common and perception of colours and contrasts may also be affected.

In the longer term it is difficult to predict how sight will be affected. Some children experience a gradual deterioration in vision before the age of six or seven. For other children and young people vision remains more stable and deteriorates only gradually. Sometimes the cornea is affected, which may be a result of the child pressing his/her hands against the eye.

The vast majority of children with the disease have no other disability.

Diagnosis

It can be difficult to make an early diagnosis of Leber congential amaurosis, but one sign may be the sluggish reaction of the pupils to light. In newborns the retina often looks normal, although in certain babies there may be abnormal pigmentation. After a few years all children with the disease show eye pigment abnormalities and their retinas have thin blood vessels. Gradually the optic disc (papilla) becomes pale. Commonly, children with Leber congenital amaurosis develop refractive errors early, usually manifesting as severe long-sightedness.

Diagnosis is confirmed using an electroretinogram (ERG), an electro-physiological examination of retinal function. When children are six or seven the examination can usually be carried out when they are awake. It is important that the diagnosis is made as early as possible. For this reason small children may need to be examined under anaesthetic. An ERG examination is also very important in establishing the type and degree of residual vision.

As more genetic mutations are identified, blood tests and DNA testing play an increasingly important role in diagnosis. About 50 per cent of diagnoses can be confirmed using DNA-based technology. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Diseases of the retina which manifest early and whose symptoms are similar to Leber congenital amaurosis may in fact be part of a syndrome or a metabolic disease. In these cases the child has additional symptoms or disabilities. Examples of these syndromes include: Bardet-Biedl syndrome, Alström syndrome, Zellweger syndrome, Refsum disease, Joubert syndrome, Infantile Neuronal Ceroid Lipofuscinoses (INCL) and familial juvenile nephronophtisis. For all these conditions except the last, information is available in the Swedish Department of Health and Welfare’s database of rare diseases.

Treatment/interventions

Today (2013) there are no reliable treatments which definitely affect the progression of the disease. Some children are treated with small supplementary doses of vitamin A. Results, however, are inconclusive. Treatment should be carried out in consultation with a paediatrician and ophthalmologist. In recent years research has shown that gene therapy can give impressive results. It not only stabilises the disease, but some vision may be restored. (See under, “Research and Development.”)

When growing up, children with the disease require regular monitoring by a paediatrician and ophthalmologist. Treatment consists mainly of alleviating symptoms and compensating as far as possible for loss of vision. Vision is measured at an eye clinic. If children develop a degree of vision, this should be identified and followed up. Visual acuity, field of vision and degree of sensitivity to dark, colour and contrasts are measured with the help of various age-related tests, the results forming the basis for a visual habilitation programme. If the child reacts to visual stimuli it is important to correct refractive errors early so that his or her vision is as good as possible. Wearing spectacles can also stop children pressing their eyes.

Every eye clinic collaborates with the habilitation team at a low vision centre. Contact with the team should be offered at an early stage. In the team are professionals with expertise on visual disabilities and their effects on health, development and everyday life. Support and treatment are provided within the medical, educational, psychological, social and technical fields. Children without sight can receive help in training in compensatory techniques, and those with very weak sight can be helped to use the sight they have. Children can try out visual aids and receive training in their use. These include magnifying glasses, spectacles for close work, binoculars, magnifying TV sets and specially-adapted computers. Spectacles with filters may improve contrast vision and decrease light sensitivity. Lighting should also be adapted. Commonly, children with Leber congenital amaurosis use braille to read.

The motor development of children with a visual disability, with or without residual vision, often diverges from the normal. A physiotherapist working with the child and the family can often help with motor problems indirectly caused by visual impairment. Improved physical awareness can be achieved by training which improves balance, strength and general physical condition.

Children and young people with the disease, and their families, may require psychological and social support both when a diagnosis is made and when different problems occur. Contact with other children, young people and families in similar situations is valuable.

All habilitation plans focus on the needs of the individual child. These plans vary over time, are drawn up in close collaboration with people in the child’s network and include information on support provided in the community.

Children with visual impairments attend the local authorities’ ordinary nurseries and schools. To ensure that children are taught according to the correct methods and with appropriate aids, school staff require the help and guidance of a teacher with training in visual disabilities. At the Resource Centre for the Visually Impaired, operating under the aegis of The National Agency for Special Needs Education and Schools in Stockholm and Örebro, there are professionals who can give advice on visual disability. (See under “National and Regional Resources in Sweden.”)

Having a visual impairment may affect both a person’s social life and choice of occupation. Much can be done to support the individual and compensate as much as possible for impaired vision. All interventions are adapted to suit the age and life style of the individual.

Practical advice

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National and regional resources in Sweden

Expertise is available at the Specialist Clinic for Congenital Diseases of the Retina, Eye Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

The Swedish National Agency for Special Needs Education and Schools (www.spsm.se) is a country-wide, public authority. The organisation’s role is to give special educational support to local and other authorities with responsibility for day care, pre-schools, schools, independent educational establishments and adult education. National resource centres with specialist expertise can carry out investigations, organise visits for children and young people and provide information and training for parents, teachers and other personnel. Swedish Resource Centres for the Visually Impaired are located in Stockholm and Örebro.

Resource Centre for the Visually Impaired - Stockholm, Rålambsvägen 32 B, Box 12161, SE-102 26 Stockholm, Sweden. Tel: +46 10 737 50 00, email: rc.syn.stockholm@spsm.se.

Resource Centre for the Visually Impaired - Örebro, Eriksbergsgatan 3, SE-702 30 Örebro. Box 9024, SE-700 09 Örebro, Sweden.Tel: +46 10 473 50 00, email: rc.syn.orebro@spsm.se.

Resource personnel

Professor Sten Andréasson, Eye Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

Chief Physician Ying Liu, Eye Clinic, Stockholm South General Hospital (Södersjukhuset AB), SE-118 83 Stockholm, Sweden. Tel: +46 8 616 10 00.

Courses, exchanges of experience, recreation

Resource Centre for the Visually Impaired in Stockholm is a national resource within the National Agency for Special Needs Education and Schools, which arranges parent training and other activities. Children with severe visual impairments and their parents attend courses before and during the preschool years. In school, they are invited to attend group visits for a few days each year. Individual assessments aiming to evaluate functional vision, general development and the consequences of impaired vision, are carried out by a multidisciplinary team. Schoolchildren may come for training on an individual basis. For contact information, see under “National and regional resources in Sweden.”

Each year the Resource Centre for the Visually Impaired participates in arranging two sporting weekends for visually impaired young people, one in the autumn for athletics and one in the spring for sports specifically for the visually impaired, such as goalball, showdown, etc.

The Swedish Sports Organization for the Disabled and The Swedish Paralympic Committee (SHIF/SPK), Idrottens Hus, SE-114 33 Stockholm, Sweden. Tel: +46 8 699 60 00, www.shif.se.

The Swedish National Association for the Active Visually Disabled organises camps and other leisure activities: Box 42122, SE-126 15 Stockholm, Sweden. Tel: +46 8 744 15 93, fax: +46 8 744 32 57, www.aktivasynskadade.org.

Organizations for the disabled/patient associations etc.

The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srfriks.org, www.srfriks.org.

The Swedish Association of Visually Impaired Young People, Sandsborgsvägen 44, SE-122 33 Enskede, Sweden. Tel: +46 8 39 92 85, email: webmaster@ungasyn.se, www.ungasyn.se.

The Swedish RP (Retinitis Pigmentosa) Association, Gotlandsgatan 44 (4th floor), Box 4903, SE-116 94 Stockholm, Sweden. Tel: +46 8 702 19 02, email: kontakt@srpf.a.se, www.srpf.a.se.

Courses, exchanges of experience for personnel

The Resource Centre for the Visually Impaired in Stockholm arranges courses for staff responsible for children with visual disabilities in pre-schools and schools. For more information, visit the website of The National Agency for Special Needs Education and Schools, www.spsm.se.

Research and development

Extensive research is under way to find the causes of the disease and, in the longer term, to offer treatment including gene therapy, retina transplantation, hematopoietic stem cell transplantation (HSCT) and dietary supplements to protect the cells of the retina (neuroprotection).

Research during recent years has indicated that gene therapy may be a successful form of treatment in the future. Gene therapy involves a harmless virus carrying the healthy gene being injected into the diseased eye. Animal trials were so successful that human trials have taken place with patients with mutations in the RPE65 gene. Recently, the results of a trial of this treatment, which involved 40 patients over a period of years, were reported. As Leber congential amaurosis is caused by a single mutation in one of several genes, the mutation must first be identified in order to plan treatment for each separate gene. The results of these trials have been so positive that currently there are research projects under way into a large number of genetic defects associated with congenital diseases of the retina. Recently, gene therapy has been carried out on a further two individuals with Leber congenital amaurosis where the mutation is on another gene, MERTK. This year (2013) is a critical one for all these trials (which have included some children from Scandinavia) when the value of gene therapy will become clear and it will be possible to see whether viable treatment is likely to be developed in the next few years.

A new approach to treating a few congenital diseases of the retina linked to defects in genes RPE65 and LRAT, involves treatment with a synthetic retionoid (11-cisd-retinal). In these early forms of retinitis pigmentosa, an important element in the visual cycle is absent. Initial trials showed a positive effect on vision which remained after treatment was completed. Clinical trials, primarily involving adults with these particular genetic mutations, are currently under way; they include Swedish subjects.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.

Literature

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2231-2239.

Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS 2009; 13: 587-592.

Colella P, Auricchio A. Gene therapy of inherited retinopathies: a long and successful road from viral vectors to patients. Hum Gene Ther 2012; 23: 796-807.

Estrada-Cuzcano A, Roepman R, Cremers FP, den hollender AI, Mans DA. Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Hum Mol Genet 2012; 15: R111-124.

den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 2008; 27: 391-419.

Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 2008; 358: 2240-2248.

Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374: 1597-1605.

Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophtalmology 2013 Mar 6. pii: S0161-6420(12)01168-2. doi: 10.1016/j.ophtha.2012.11.048. [Epub ahead of print]

Traboulsi EI. The Marshall M Parks memorial lecture making sense of early-onset childhood retinal dystrophies. The clinical phenotype of Leber congenital amaurosis. Br J Ophthalmol 2010; 94: 1281-1287.

Weleber RG. Infantile and childhood retinal blindness: a molecular perspective (The Franceschetti Lecture). Ophthal Genet 2002; 23: 71-97.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: retinitis pigmentosa

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews”, then “Titles”)
Search: leber congenital amaurosis

Swedish Ophthalmological Society, (SOTA). Material on inherited diseases of the retina, http://swedeye.org/wp-content/uploads/SotA_RP.pdf

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Lena Jacobson, Astrid Lindgren Children’s Hospital, Stockholm, Sweden.

The revision of the material was carried out by Professor Sten Andréasson, Skåne University Hospital, Malmö.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2013-12-27
Version: 2.0
Publication date of the Swedish version: 2013-09-24

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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