Hereditary Disorders of Neuro Ophthalmic Relevance

D. Besch

Hereditary disorders of importance for neuro-ophthalmology include genetically inherited disorders of the posterior segment and afferent visual pathway that characteristically present as visual field defects, visual acuity loss, strabismus, or even complete blindness. These disorders have significant social and economic importance with lifelong consequences for the afflicted patient. The prevalence of inherited retinal disorders is approximately 20 cases per 100,000 people.

Decoding of the human genome has been the most important single advance in the study of inherited disorders. In the last 16 years, 132 genes of significance for the development of retinal degenerations and optic atrophy have been identified, and 53 of them have been mapped to their chromosomal locations (as of January 2007, according to the Retinal Information Network: http:/ Retnet/). Using the various techniques of molecular genetics, genetic defects could be located, to specific chromosomal regions (mapped loci), often without knowing precisely which gene is at fault. Additionally, specific functional regions of a DNA segment (= gene) could be identified to carry the changes (mutations) that encode for the traits of a particular disease (■ Fig. 18.1).

It is now recognized that mutations in various, separate genes can be expressed in phenotypes that appear to be identical disorders, as for example with retinitis pigmentosa. Alternately, it is known that a variety of differing mutations within a single gene can produce disorders that appear to be entirely different diseases. A few inherited ocular diseases have been traced well enough so that their specific biochemical changes in cellular metabolism are known, and the mechanism that produces their phenotypic expression is fully understood. The changes in cellular metabolism caused by the genetic defect then produce the various morphological and visibly recognizable signs of disease in the retina and/or the afferent visual pathway.

Specific diagnosis of hereditary ocular diseases require; very careful history taking, recognition of ophthalmic signs and typical visual function losses, collection of genetic information (family history of inherited disorders and identification of carriers), associated symptoms, and appropriate laboratory testing.

Fig. 18.1. Location of a gene. Diagram of chromosomes in a cell, of a particular chromosomal region mapped loci, and a functional DNA segment (identified gene). (Adapted from: C. Fesch: Genetische Tests. Fischer, Frankfurt 2000)

Therapeutic Options

Despite having a better understanding of genetic mutations and the disease patterns they cause, there have been to date no discoveries of treatments that can correct the damage to the underlying metabolic processes or reverse the course of their associated loss of visual function. There have been some plausible reports of partially effective treatment of various forms of retinal dystrophies with the use of vitamin therapy. Thus, for specific types of retinitis pigmentosa the use of vitamin A palmitate is now recommended, and mi-tochondrially inherited abnormalities of respiratory enzymes, such as in Leber's hereditary optic neuropathy, may benefit from correction of low levels of vitamin B12. In addition, exogenous risk factors that further burden an already-weak cytochrome oxidase chain should be avoided, such as foods containing trace levels of cyanide, abuse of alcohol, and exposure to nicotine.

Lens filters, for protection from higher levels of light and improvement of contrast sensitivity, are a rational option that can be of help in the management of some hereditary retinal diseases. Additionally, cataract extraction at an appropriate time and the use of magnifying reading lenses might improve visual acuity in some cases.

Experiments with various animal models of retinal disease and histologic study of human retinal tissues in recent years have brought to us a better understanding of the pathological changes that characterize inherited retinal degenerations. Eexperiments are underway to study the feasibility of the electronic retinal implants, transplantation of pigment epithelium or photoreceptor tissue/cells as well as of use of neuroprotective growth factors, and the potential use of somatic gene therapy.

Rare retinal dystrophies, such as Refsum's disease, gyrate atrophy, or abetalipoproteinemia (Bassen-Kornzweig syndrome) are metabolic disorders that can be partially countered with vitamins and dietary changes, which can even reverse some of the visual symptoms. For other inherited disorders, such as retinoblastomas, von Hippel

Lindau syndrome, and Alport's syndrome some conventional therapies are known to be helpful, including surgery, irradiation, cryotherapy, and laser therapy.

Systemic disorders can present initially with ocular signs and/or symptoms, leading to an early diagnosis of such diseases as pseudoxanthoma elasticum and familiar polyposis. This sometimes provides the opportunity for early use of treatment strategies, such as colectomy for the avoidance of bowel carcinomas in patients with familiar polyposis.

Tabular Summary of Hereditary Disorders of the Posterior Segment and Afferent Visual Pathways

The table below that summarizes the features of hereditary ocular diseases of the retina and optic nerve has been restricted to the most important entities. For a more complete reference, the resources listed in ■ Table 18.1 provide a rich source of additional information held in on-line databases.

■ Table 18.2 briefly lists the typical symptoms for each disease and gives estimates of the frequency of each disorder and its mode of inheritance.

In addition, gene locations and genes that have already been identified are listed (as of 2003). As an example, chromosome 6p21.1 is the locus for the RDS/peripherin gene (■ Fig. 18.2): The gene was localized on chromosome 6, the short arm (p = short arm, q = long arm), in region 21.1 (arrow).

Table 18.1. Databases and Internet addresses with useful information about hereditary ophthalmic disorders

Online Mendelian Inheritance in Man (OMIM):

Retinal Information Network (RetNet):

Retina International's Scientific Newsletter:

VMD2 Mutation Database:

A human mitochondrial genome database:

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