HOW DO PATIENTS WITH NEURAL GENETIC BLINDNESS PRESENT?

Genetic blinding diseases may manifest with isolated visual loss or with vision loss as the most prominent manifestation. For example, a patient with bilateral progressive vision loss and a clinical picture of retinitis pigmentosa may, on further questioning, complain of weakness and ataxia leading to a diagnosis of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). Such patients with primarily visual symptoms generally present to the ophthalmologist, although other features commonly require neurological consultation.

In some patients with slowly progressive vision loss with an onset in childhood or early adulthood, ophthalmological findings may be subclinical. Such patients may discover reduced visual acuity on a vision screening test, whether at school or when obtaining a driver’s license. Such patients are then referred for ophthalmological investigation.

In other cases, patients with primarily neurological complaints of weakness, numbness, or ataxia may present to the neurologist with a peripheral neuropathy and not be aware of any significant visual loss. An ophthalmological examination might demonstrate a mild bilateral optic neuropathy and suggests Charçot-Marie-Tooth syndrome.

Whether patients with a genetically blinding disease present to the ophthalmologist or the neurologist, it is important that patients in whom a genetically blinding disease is suspected undergo a complete evaluation.

CLASSIFICATION OF GENETIC DISEASE

Genetically blinding disorders may be classified by localization of vision loss, age of onset, pattern of inheritance, or presence of other symptoms. No single classification is entirely satisfactory. From a clinical point of view, all of these parameters are essential to establishing the diagnosis. We have organized this discussion based on whether the disease primarily affects the retina or optic nerve and the age of onset. Those disorders with prominent neurological or systemic involvement are considered separately.

LOCALIZATION IN THE VISUAL SENSORY SYSTEM

Vision loss may occur anywhere in the neural visual sensory system including the retina, optic nerve, chiasm, optic tract, lateral geniculate nucleus, visual radiations, or visual cortex. Most genetic causes of blindness affect the retina or optic nerve. Localization to the retina or optic nerve can usually be confirmed by a comprehensive ophthalmological evaluation but may require ancillary testing. These disorders are typically bilateral and associated with multiple parameters of decreased visual function: visual acuity, color vision, and visual field. The primary distinction between retinal and optic nerve disease is made on ophthalmoscopy with direct observation of the pathology. In several instances, there may no visible abnormalities on ophthalmoscopy, and electrophysiological evaluation with electroretinography (ERG) and visual evoked potential (VEP) is critically important for correct localization.

AGE AT ONSET AND COURSE

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.

EVALUATION

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.

RETINAL DISEASES—CONGENITAL

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

Figure 22-1 Ophthalmoscopic appearance of the retina in a patient with Leber’s congenital amaurosis caused by mutations in CRB1.

(Courtesy of I. H. Maumenee.)

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

Figure 22-2 In a patient with albinism, transillumination of the globe demonstrates the absence of pigment in the iris (left). On ophthalmoscopic examination of the retina, the lack of pigmentation in the retinal pigment epithelium allows easy visualization of the choroidal vessels (right).

(Courtesy of I. H. Maumenee.)

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.

Figure 22-3 Fundus appearance of a total retinal detachment in a patient with Stickler’s syndrome.

(Courtesy of I. H. Maumenee.)

RETINAL DISEASES—ONSET IN CHILDHOOD AND ADULTHOOD

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