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The study of genetic diseases offers an opportunity to understand the pathophysiology at the molecular level. Identification of genetic defects that lead to clinical syndromes and how a syndrome can be caused by a variety of genetic defects offer powerful insight. In addition, such insights offer a rationale for therapeutic target development.

The visual sensory system has been an area of genetic investigation by well-known pioneers including Horner, Leber, Nettleship, Sorsby, Tay, Usher, and Waardenberg. Many basic genetic mechanisms were initially demonstrated in ocular diseases, including X-linked recessive inheritance for color blindness, cytoplasmic inheritance of optic atrophy, inactivation of a single X chromosome in the mosaic pigmentary pattern in females heterozygous for ocular albinism, the two-hit hypothesis of hereditary retinoblastoma, and triallelic inheritance in Usher’s syndrome.

A variety of genetic diseases may lead to blindness by affecting the entire globe, primarily the anterior segment (cornea and lens), or primarily the posterior segment (retina and optic nerve) of the eye. Disorders of the globe are often caused by abnormal closure of the fetal fissure resulting in colobomatous malformations and microphthalmia. Nanophthalmos refers to a small but normally formed eye. Anophthalmia, or absence of the eye, results from failure of outgrowth of the primary optic vesicle. Congenital genetic blinding disorders of the anterior segment include congenital cataracts; the Axenfeld-Riger spectrum, which encompasses a variety of anterior segment malformations involving the cornea, anterior chamber angle, and the iris; and Peter’s anomaly, consisting of a central corneal leukoma with varying amounts of iris and lens attachments. Progressive genetic disorders affecting the anterior segment include a variety of corneal dystrophies with gradual deposition of amyloid, mucopolysaccharide, or other components into the cornea. Neural genetic blindness arises from disorders affecting the retina and optic nerve. To a lesser extent, retrogeniculate genetic disorders may affect the vision but often have other neurological manifestations as well. Retina and optic nerve disorders are the focus of this chapter. A highly recommended and thorough discussion of ophthalmic genetics is available in Traboulsi (1998).


From a diagnostic point of view, it is useful to consider the age at onset of vision loss. The presence of nystagmus is critical in determining the onset of a potentially blinding genetic disease. Bilateral congenital loss of vision is associated with nystagmus. Nystagmus develops whether the vision loss is caused by genetic or nongenetic mechanisms. Furthermore, nystagmus develops whether the vision loss is due to corneal, lens, retinal, or optic nerve abnormalities. Thus, the nystagmus is thought to arise from abnormal ocular motor adaptation to impaired sensory input. The reason for the development of nystagmus is not understood. Congenital nystagmus most often is caused by Leber’s congenital amaurosis, optic nerve hypoplasia, and ocular albinism. Approximately 10% of patients with congenital nystagmus have no apparent abnormality of the visual sensory system and are referred to as congenital idiopathic or congenital motor nystagmus. The vision in such patients is generally much better than those patients in whom nystagmus is caused by congenital diseases of the retina or optic nerve, probably because the visual loss in the former group of patients is secondary to the nystagmus itself, rather than its cause.

Although many well-recognized genetic disorders have their onset and clinical presentation in infancy, others may not be recognized until childhood or early adulthood. Such patients may have subclinical disease or only notice difficulty seeing at night. These disorders are typically slowly progressive and can lead to diagnostic confusion in the early stages when findings are mild. A variety of ancillary testing including electrophysiology and fluorescein angiography can be useful in making a diagnosis.

Most genetic diseases are characterized by slowly progressive vision loss. A notable exception to this is Leber’s hereditary optic neuropathy (LHON), which has an acute presentation and may be confused with optic neuritis.


Patients should undergo a complete ophthalmic examination. Refractive errors should be noted as patients with congenital stationary night blindness (CSNB) are myopic whereas patients with Leber’s congenital amaurosis (LCA) are hyperopic. The pupil reaction is of interest. Although loss of vision is commonly associated with a reduction in the pupil light reflex and sluggish pupils, the pupils in some congenitally blinding disorders actually constrict in darkness rather than dilate. This finding, referred to as paradoxical pupils, occurs in LCA and CSNB. Color vision testing is abnormal in patients with achromatopsia and cone dystrophy. Additionally, the pattern of visual field loss is often characteristic of the underlying abnormalities. Retinitis pigmentosa tends to produce progressive peripheral constriction of visual fields, whereas cone dystrophy and optic nerve disorders tend to produce central scotomas. Slit lamp biomicroscopy is used to examine for iris transillumination defects by shining a beam of light through the pupil and observing to see if it is reflected through defects in the iris due to lack of pigmentation, as seen in ocular albinism. Ophthalmoscopic examination may reveal a pigmentary retinopathy in patients with retinitis pigmentosa or bilateral optic atrophy in a patient with dominant optic atrophy. In other cases, ophthalmoscopic findings are mild. Many patients with LCA who present in infancy have a normal fundus. Adults with CNSB often have a normal-appearing fundus. ERG is critical in distinguishing these disorders. In macular disease, a multifocal ERG, which can detect focal retinal defects, is more sensitive than a full-field ERG.


Many of the congenital blinding disorders of the retina involve proteins that are members of the phototransduction cascade, primarily affecting photoreceptors. Other disorders affect the structural relationship between the neural retina and the vitreous.

LCA is an autosomal recessive syndrome characterized by significantly reduced vision before age one, nystagmus, paradoxical pupillary reactivity, and retinal degeneration. This syndrome has a prevalence of 3:100,000 children and is a common cause of congenital nystagmus. Six LCA-causing genes have been identified, which account for approximately one half of the cases.1 These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The clinical appearance is varying with fundus findings ranging from a retinitis pigmentosa picture with bony spicules to a salt and pepper appearance (Fig. 22-1). Electroretinography (ERG) demonstrates a markedly reduced or nonrecordable scotopic and photopic response, confirming the diagnosis. Although no therapy is presently available, promising gene-based interventions have demonstrated long-term rescue of vision as assessed by psychophysical, behavioral, and molecular biology studies. In a naturally occurring LCA animal model, the RPE65-/- dog, recombinant adenoassociated virus carrying wild-type RPE65 successfully restored visual function.2

Achromatopsia is a rare retinal disorder characterized by a complete absence of cone photoreceptor function. In accordance with the trichromatic theory of vision, individuals with normal color vision can match any color with a combination of three primary colors: red, green, and blue. Dichromats who are missing either the red (protanopes) or green (deuteranopes), but retain the blue cone function, can only match colors with two primary colors. The red (OPN1LW, opsin 1, long wave sensitive) and green (OPN1MW, opsin 1 medium wave sensitive) photopigments are encoded on the long arm of the X chromosome and, as such, these disorders are transmitted in a pattern of X-linked inheritance. The blue (OPN1SW, opsin 1, short wave sensitive) photopigment is encoded on chromosome 7. Achromats present in infancy with reduced vision, photophobia, total color blindness, nystagmus, and a normal-appearing retina. Achromatopsia refers to a spectrum of disease encompassing complete achromatopsia (rod monochromacy), in which there are no cones; atypical rod monochromacy, in which there are some functioning cones; and blue cone monochromacy, where the red and green photopigments are absent but the blue photopigment is functional. Psychophysical testing in such patients must be performed after age 10 in order to get reproducible results. Genes associated with achromatopsia include CNGA33 and CNGB3,4 encoding the α and β subunits of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A third gene identified in achromatopsia is GNAT2,5 encoding the cone specific α unit of transducin, a G protein of the phototransduction cascade.

Aniridia is a syndrome in which the most prominent manifestation is absence or hypoplasia of the iris. Importantly, visual acuity is reduced due to hypoplasia of the fovea, macula, or optic nerve. Patients present with reduced visual acuity, elevated intraocular pressure, and nystagmus and may develop cataract, glaucoma, keratopathy, strabismus, and amblyopia. Aniridia is caused by mutations in PAX6, a homeobox gene on chromosome 11.6 The homeobox encodes the homeodomain, a protein domain that binds DNA and regulates the transcription of other genes. Aniridia is inherited as an autosomal dominant disorder. WAGR syndrome consists of Wilm’s tumor, aniridia, genitourinary abnormalities, and retardation, resulting from a deletion on chromosome 11p.

Albinism is traditionally divided into oculocutaneous albinism and ocular albinism. Oculocutaneous albinism is autosomal recessive and has been divided into tyrosinase-positive and -negative forms. Tyrosinase catalyzes three steps in a series of reactions in the melanosome that lead to the formation of melanin from its precursor tyrosine. Major oculocutaneous albinism syndromes include Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, which are inherited in autosomal recessive manner. Nettleship-Falls ocular albinism is an X-linked recessive disorder characterized by reduced visual acuity, congenital nystagmus, transillumination defects of the iris (Fig. 22-2), hypopigmentation of the uveal tract and retinal pigment epithelium, hypoplasia of the fovea, and abnormal decussation of optic nerve fibers through the chiasm. Strabismus and refractive abnormalities are common. Ocular albinism is caused by mutations in OA1, a member of the G protein-coupled receptor superfamily.7

Hereditary vitreoretinopathies are characterized by degenerative changes involving the vitreous and retina. These include familial exudative vitreoretinopathy, Goldmann-Favre syndrome, Stickler’s syndrome, Knobloch’s syndrome, and Norrie disease. Familial exudative vitreoretinopathy (FEVR) has features similar to retinopathy of prematurity but without premature birth or supplemental oxygen. This autosomal dominant disorder is caused by mutations in the frizzled-4 gene (FZD4)8 and is characterized by peripheral retinal vascular nonperfusion, exudative retinal detachment, and proliferative, cicatricial vitreoretinopathy. With severe loss of vision, patients develop nystagmus and strabismus. Goldmann-Favre syndrome is an autosomal recessive disorder caused by mutations in the nuclear receptor gene NR2E3 with characteristic features of retinitis pigmentosa along with central and peripheral retinoschisis, a splitting of the retina. Stickler’s syndrome, a progressive hereditary arthro-ophthalmopathy, is characterized by high myopia, vitreous degeneration, and retinal detachment (Fig. 22-3) in association with orofacial abnormalities such as Pierre-Robin sequence and musculoskeletal abnormalities such as arthritis, scoliosis, and arachnodactyly. It is inherited as an autosomal dominant disorder and caused by mutations in type II collagen (COL2A1). Knobloch’s syndrome is characterized by high myopia, vitroretinal degeneration with retinal detachment, and occipital encephalocele and is caused by a mutation in collagen XVIII (COL18A1). Norrie’s disease is characterized by mental retardation and bilateral retinal detachment presenting early in life. It is inherited as an X-linked disorder caused by mutations in the Norrie gene, which is thought to interact with the FZD4 gene.


Retinitis pigmentosa (RP) encompasses a variety of disorders that primarily affect rod photoreceptors. Although a pigmentary retinopathy may occur as a feature of a variety of multisystem diseases discussed at the end of the chapter, it may also occur as an isolated disorder of the retina. Initial vision loss in RP occurs in the midperipheral visual field and initial retinal pathology in the postequatorial fundus. In contrast, cone dystrophies refer to those photoreceptor disorders primarily affecting cones and initially involving the macula. There is considerable overlap between these entities. Inability to see as clearly in dim light as in bright light (nyctalopia) is the initial symptom of the rod dystrophies, followed by loss of peripheral vision. The fundus initially has a gray discoloration at the level of the retinal pigment epithelium (RPE) in areas corresponding to vision loss. With time, pigmented cells migrate into the retina aggregating around blood vessels leading to the characteristic bone spicule appearance and a “waxy” pallor of the optic nerve.

The most common hereditary form of RP is autosomal recessive (60%), followed by autosomal dominant (10% to 25%) and X-linked (5% to 18%). The X-linked and recessive forms are more severe than autosomal dominant RP. The first gene determined to be mutated in RP was rhodopsin.9 Other genes include peripherin, tissue inhibitor of metalloproteinase, and geronyl-geronyl transferase. More than 20 genes causing RP have been identified.

In contrast to retinitis pigmentosa, patients with cone dystrophies

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