Retinitis pigmentosa

SURVEY

OF OPHTHALMOLOGY

MAJOR

VOLUME

33. NUMBER

3. NOVEMBER-DECEMBER

1988

REVIEW

Retinitis Pigmentosa ROBERTA A. PAGON, M.D.

Departments of Pediatrics and Ophthalmology, University of Washington School of Medicine, and Division of Medical Genetics, Children’s Hospital and Medical Center. Seattle, Washington

Abstract. Retinitis pigmentosa is a clinically and genetically heterogeneous group of hereditary disorders in which there is progressive loss of photoreceptor and pigment epithelial function. The prevalence of retinitis pigmentosa is between l/3000 and 115000 making it one of the most common causes ofvisual impairment in all age groups. The natural history, differential diagnosis, diagnostic clinical and electrophysiologic findings are reviewed. Generalizations about the different genetic subtypes of retinitis pigmentosa are reviewed along with the uses of DNA probes for linkage studies. Syndromes in which retinitis pigmentosa is a manifestation are summarized. (Surv Ophthalmol 33:137-177, 1988)

Key words. disorders degeneration Retinitis

cone dystrophy cone-rod dystrophy metabolic disorders night blindness retinitis pigmentosa skeletal dysplasia l

l

l

l

pigmentation

l

is the

term

for

and Natural

dark adaptation neurologic disorders vitamin A

l

hereditary retinal l

l

degeneration” will be used synonymously to refer to the retinal changes of retinitis pigmentosa. “Tapetoretinal degeneration” is another generic term, which will not be used here. Although there are no established diagnostic criteria for retinitis pigmentosa, attempts have been made to establish guidelines for evaluation of patients known or suspected to have retinitis pigmentosa. 224The following represents a consensus of participants in a 1982 symposium. The diagnosis ofretinitis pigmentosa is established when the following findings are present (Table 1): 1) bilateral involvement; 2) loss of peripheral vision; 3) rod dysfunction evidenced by elevated rod final threshold on dark adaptation andlor rod responses on ERG that are reduced in amplitude and prolonged in implicit time or are nondetectable; 4) progressive loss in photoreceptor function. While the fundus appearance in advanced retinitis pigmentosa is typical, these changes reflect longstanding retinal degeneration and need not be present to make the diagnosis.?4” On the other hand, the fundus findings are instrumental in distinguish-

“a set of

progressive hereditary disorders that diffusely and primarily affect photoreceptor and pigment epithelial function.“22” The metabolic basis of most of the disorders called retinitis pigmentosa is not yet known. Of the many disorders encompassed by the term retinitis pigmentosa, some affect only the eye and others are systemic disorders. This article reviews the diagnosis, natural history, genetics and differential diagnosis of the group of disorders called retinitis pigmentosa. Other reviews include the work of Merin and Auerbach,235 Heckenlively,‘hsd and Newsome.“““a

I. Diagnosis

l

l

History

Retinitis pigmentosa is a semantically incorrect but widely accepted term describing a group of clinically similar retinal degenerations. Although the term retinitis means “inflammation of the retina,” the disorders included under the rubric are hereditary, not inflammatory conditions. “Rodcone dystrophy” has been used synonymously with retinitis pigmentosa by some investigators.g6 In this paper the terms “retinal dystrophy” and “retinal

ing retinitis 137

pigmentosa

from

other

retinal

dystro-

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Surv Ophthalmol

33(3) November-December

phies, such as choroideremia and that have similar clinical findings retinal appearances.

gyrate atrophy, but distinctive

A. OPHTHALMOLOGIC

EVALUATION

PATIENTS

TO HAVE ONE OF THE

SUSPECTED

FORMS OF RETINITIS

1988

OF

PIGMENTOSA

1. History A complete history of visual symptoms should include information regarding the nature of the earliest symptoms, the age of onset, and progression. The initial symptom is usually defective dark adaptation or “nightblindness.” (“Nyctalopia,” defined as “nightblindness or inability to see as well as persons with normal sight at night or in a dim light,“3” will not be used in this paper because of confusion with “hemeralopia,” which literally but is used synonymously means “day blindness,” with nyctalopia, especially in Europe.s”) If patients with retinitis pigmentosa do not volunteer a history of faulty dark adaptation, direct questioning about the speed of dark adaptation in certain circumstances may cause patients to recognize the symptom of delayed adaptation to dim light. Careful questioning often can elicit such a history starting in childhood or adolescence if patients are asked to recall difficulties with outdoor activities at dusk or indoor activities at night with minimal lighting. In a retrospective study of patients from 456 families the symptom of nightblindness occurred at an earlier age in those patients with X-linked and autosomal dominant retinitis pigmentosa than those with autosomal recessive and simplex (for definition see Section IV) retinitis pigmentosa.40 By age 20 years, 87% of patients with X-linked retinitis pigmentosa and 75% of patients with autosomal dominant retinitis pigmentosa had symptoms, whereas only 61% with autosomal recessive inheritance and 64% of simplex cases were symptomatic. By age 30 years, 100% of those with X-linked, 89% with autosomal dominant, but only 74% of autosoma1 recessive and 79% simplex were symptomatic.

TABLE

1

Diaffnostic Criteria: Retinitis Pipnentosa 1) Bilateral involvement 2) Loss of peripheral vision 3) Rod dysfunction a. dark adaption: elevated rod final threshold or _. b. electroretinogram (ERG): rod responses with re-

duced amplitude and prolonged implicit time or non-detectable 4) Progressive loss in photoreception function

PAGON

However, retrospective determination of the age of onset of any symptom tends to reflect the time at which a symptom was first recognized as abnormal, rather than the age at which it first appeared or caused disability. Hence, such retrospective information needs to be interpreted with caution. In contrast, patients rarely note a loss in peripheral vision as an early symptom, although they may be considered “clumsy” before constricted visual fields are detected. It should be noted that patients who present with initial symptoms of photopsia (sensation of lights flashing), abnormal central vision, abnormal color vision, or marked asymmetry in ocular involvement may not have retinitis pigmentosa, but another retinal degeneration or retinal disease. 2. Ocular

Examination

The purpose of the ocular examination in a patient suspected of having one of the forms of retinitis pigmentosa is to identify those findings that support the diagnosis and those that may suggest another diagnosis. The ocular examination should include measurement ofbest corrected visual acuity, refraction, examination ofthe anterior segment and measurement of intraocular pressure. Attention also should be given to the lens, vitreous, optic disc, retinal vessels, macula and retinal periphery. 3. Visual

Acuity

Central visual acuity is usually preserved until the end stages of retinitis pigmentosa. Some investigators have found a general correlation between visual acuity at a given age and genetic subtype.‘15 Fishman et al determined that patients with autosomal dominant disease had the best prognosis, with the majority ofthose under 30 years having visual acuity of 20130 or better,‘13 whereas the X-linked recessive group had the worst prognosis, with all patients over the age of 50 years having a visual acuity less than 20/200.“” Autosomal recessive and simplex cases were intermediate in severity. Pearlman, on the other hand, found no correlation between central visual impairment and genetic subtype.‘“” In a retrospective study to determine the age of onset and rate of progression of visual loss, Marmo? studied the visual history of 59 eyes of patients with “autosomal recessive” retinitis pigmentosa. He determined that the median time for deterioration in visual acuity from 20140 to 20/200 was about six years, the change occurring in less than 10 years in all but a few patients. The number of eyes with mild to moderate impairment of visual acuity remained relatively small (10%) in any age group, suggesting that visual acuity decreases rapidly and does not remain in the mid-range for long.

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In a prospective study of 94 patients over a threeyear period, Berson et a14’documented little change in visual acuity despite significant loss of visual field, and decrease in amplitude of both fovea1 cone electroretinograms and full-field electroretinograms. Loss of central visual acuity is caused most commonly by direct macular involvement from the retimtis pigmentosa, macular cysts, or posterior subcapsular cataracts. Visual acuity loss was not related to age of onset, rate of progression or initial visual acuity in these studies,““~Z22~ZW but was related to duration of night blindness in another study.“’ Utilizing the Farnsworth-Munsell 100 Hue Test and absolute fovea1 threshold, Massofet alz3’detected disorders of fovea1 vision at all stages of retinitis pigmentosa. These sensitive tests of cone function documented early cone involvement despite normal visual acuity. These authors found a high correlation between the loss of fovea1 color discrimination and the loss of visual field, suggesting that fovea1 and peripheral visual function are lost simultaneously. 4. Refractive Error Sieving and Fishman”“” found myopia in 75% of 268 eyes of retinitis pigmentosa patients compared to 12%~ of the normal population. Berson et al’” detected myopia in at least 10% of patients from 456 families. Both studies found myopia to be more common in the X-linked group. Although generalizations about refractive error in genetic subtypes of retinitis pigmentosa can be made, refractive error is not sufficiently specific to permit genetic classification in patients with an uninformative family history. 5. Anterior

Segment and Ocular

Tensions

Ocular tensions are usually normal even in endstage disease, although some authors have suggested a higher-than-expected incidence of glaucoma in retinitis pigmentosa.“’ 6. Lens

Posterior subcapsular cataracts characterized by yellowish crystalline changes within the peripheral lens cortex in the visual axis are common in all forms of retinitis pigmentosa.‘“’ Most patients with visual fields of more than 10” are not incapacitated by such posterior subcapsular cataracts, but some may benefit from lens extraction.“‘.“‘H’i” Of 225 patients with various genetic types of retinitis pigmentosa, Heckenlively’“” found no cataracts in about 60% and visually significant cataracts or aphakia in only 5- 14% ofthe total group. Merin”” reported similar findings in 92 patients. Fishmen et al”” determined that 53%’ of 338 retinitis pigmentosa patients showed a posterior subcapsular cata-

ract (or were aphakic). Severity of the cataract correlated with patient age in all the studies. HeckenlivelyltiY found no correlation with genetic subtype, amount of visual field loss or visual acuity, whereas Fishman et al”s,‘no and Berson et a14”found cataracts to be more prevalent in patients with X-linked retinitis pigmentosa. Visual loss in agematched patients with small or no posterior subcapsular cataracts was not significantly different from that in patients with more severe lens changes.“’ This observation supported the contention of Fishman et al’2’.‘2’ that visual acuity loss in retinitis pigmentosa is more likely to occur as a result of macular involvement than cataract. The cause of cataract formation in retinitis pigmentosa is unknown. Some have postulated a causative role for the “pseudoinflammatory” pigmented cells in the vitreous.?.” Ultrastructurally the cataracts of retinitis pigmentosa are not unique,‘“’ except for focal epithelial degeneration which may cause osmotic instability.‘“” Lens subluxation has been described occasionally in patients with a retinal dystrophy.“’ 7. Vitreous The great majority of retinitis pigmentosa patients have changes in the vitreous, which Pruett:“’ has classified into four groups: Stage I - fine colorless dust-like particles evenly distributed throughout the vitreous; Stage II - posterior vitreous detachment; Stage Ill - vitreous condensation with the appearance of a matrix or reticulum of spindle-shaped condensations and/or cottonball-like opacities; and Stage IV - collapse of the vitreous with greatly reduced volume. Fine particles were found evenly distributed throughout the vitreous regardless of the stage of vitreous degeneration. By transmission electron microscopy they have been identified as free melanin pigment granules, pigment epithelium, uveal melanocytes, retinal astrocytes and macrophage-like cells.” In 116 eyes of retinitis pigmentosa patients examined by Pruett,‘:J there was a general tendency for stage to correlate with age, with severity of disease increasing with age, although some Stage Ill and IV patients were less than 20 years old. Pruett found no correlation between the stage of error, mode of degeneration and sex, refractive inheritance, visual acuity, or presence of cataracts, but there was some correlation with visual field loss. The cause of the vitreous changes is unknown.“” 8. Retina The intraretinal pigment deposition (bone spicule pigmentation) and arteriolar narrowing that characterize the fundus appearance in patients with all types

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Surv Ophthalmol 33(3) November-December 1988

PAGON

Fig. 1. Left: Peripheral fundus changes in a 7-year-old boy with X-linked retinitis pigmentosa. Note the patchy areas of retinal pigment epithelial loss (large arrows) and scattered intraretinal pigment clumping (small arrows). Right: Posterior fundus. Note the somewhat attenuated retinal vessels, lack of retinal pigment thinning or intraretinal pigment clumping, and normal light reflexes off the inner retinal surface.

ofretinitis pigmentosa represent advanced changes of retinal degeneration and need not be present to make the diagnosis of retinitis pigmentosa. The fundus appearance in retinitis pigmentosa depends on the stage of the retinal degeneration. In the earliest stages electroretinography reveals defective rod responses, but the patient may be asymptomatic with a normal appearing fundus. The earliest observed changes in the fundus are arteriolar narrowing, fine dust-like intraretinal pigmentation and loss of pigment from the pigment In the past the term retinitis epithelium. 28.265,315 pigmentosa sine pigment0 was applied when the retina appeared normal despite documented abnormalities of photoreceptor function; however, this term is now regarded as confusing because it implies a separate disorder rather than the early stages of retinitis pigmentosa.2”5 As photoreceptor deterioration progresses, there is increasing loss of pigment from the pigment epithelium with intraretinal clumping of melanin, appearing most often as coarse clumps in a “bone spicule” configuration (Figs. l-3). Progressive changes in the amount and location of intraretinal pigment have been observed even over a short term; Berson et al” documented such changes in 38 of 7 1 patients (54%) followed with fundus photographs over a S-year period. The mottled fluorescein pattern seen with more advanced fundus changes is caused by loss of pigment from the retinal pigment epithelium and by intraretinal pigment migration.138 Retinal vessel attenuation and waxy pallor of the optic nerve become apparent in patients with advanced retinitis pigmentosa. The cause of the retinal vessel attenuation is unknown, but it appears to be a secondary change and not the primary disease

process. In early retinitis pigmentosa, fluorescein angiography reveals a normal pattern of choroidal fluorescence and normal timing of the retinal arteriolar and venous phases.‘38 Although arteriolar narrowing is an early finding in retinitis pigmentosa, the results of fluorescein angiography suggest that photoreceptor damage antedates disturbance of the retinal circulation. It has been proposed that retinal arteriolar constriction is the result of (1) increased intravascular oxygen tension due to decreased oxygen consumption by the degenerating outer retinal layers; (2) closer proximity of the retinal vascular network to the choroidal circulation as a result of retinal thinning.2’4 Choroidal changes in advanced retinitis pigmentosa generally include loss of the choriocapillaris and eventually all but the largest choroidal vessels. Early in the course of all types of retinitis pigmentosa, visual acuity is usually normal and the macula appears normal. As the retinal degeneration progresses in retinitis pigmentosa, there may be atrophy of the pigment epithelium and pigment disturbance directly in the macula. In contrast, cone-rod dystrophies typically have early loss of central vision. In this paper, cone-rod dystrophies are not considered “retinitis pigmentosa” and are discussed separately in Section III.A.3. Other retinal changes include white dots deep in the retina at the level of the pigment epithelium. Several histologic changes account for these: 1) typical drusen at the level of Bruch’s membrane; 2) amorphous deposits between the retinal pigment epithelium and its basal 1amina;68,236and 3) reduplication of the retinal pigment epithelium. These deposits are believed to be a nonspecific manifes-

RETINITIS PIGMENTOSA

Fig. 2. Fundus of 21-year-old woman with simplex retinitis pigmentosa. (Same fundus one year later is shown in left cover photo.) Retinal changes are more marked than in Fig. 1. Note narrowing of retinal arterioles, extensive areas ofretinal pigment epithelial loss with intraretinal pigment clumping, and pallor of the disc. The macula is normal.

tation of pigment epithelial degeneration and may account for the retinal appearance termed “retinitis punctata albescens,” which is considered a manifestation of retinitis pigmentosa.?“” 9. Macula Fishman et al”’ reported three types of macular lesions in 31 retinitis pigmentosa patients: Group 1 - 58%~ of patients had atrophy of the macular area with thinning of the retinal pigment epithelium and mottled transmission defects on fluorescein angiography. All of the patients in this group had moderate to advanced changes of retinitis pigmentosa in the midperiphery. Group 2 - 19%’ showed cystic lesions or partialthickness holes within the macula with radial, inner

111

Fig. 3. Posterior fundus of patient with advanced retinitis pigmentosa. Note marked retinal arteriolar narrowing (arrows) and marked intraretinal pigment clumping near the disc.

retinal traction lines and/or various degrees of preretinal membranes causing a “surface wrinkling phenomenon” (Fig. 4.4). ,4mong these patients the overall clinical severity of the retinal degeneration varied, but several had minimal retinal changes in the periphery. These macular changes were not atrophic and fluorescein angiography showed neither fluorescence nor leakage from perifoveal capillaries (Fig. 4B). Group 3 - 23%) of patients had cystoid macular edema and evidence of increased capillary permeability on fluorescein angiography (Fig. 5). These patients, like those in Group 2, had minimal or no pigmentary changes in the midperiphery, suggesting more recent onset or less severe retinitis pigmentosa. Fishman et al”’ concluded that there are probably two mechanisms giving rise to central visual loss in retinitis pigmentosa: disease of the macular

4. Left: Cystic macular lesion in moderately advanced retinitis pigmentosa. Right: Fluorescein shows transmitted hyperfluorescence but no leakage.

Fig.

angiogram

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33(3) November-December

1988

photoreceptors and retinal pigment epithelium (Group 1) and partial-thickness holes or cysts in the macula in patients with preserved photoreceptor function (Groups 2 and 3). In a second study to assess the incidence of macular lesions, Fishman et alIz determined that 69 of 110 patients (63%) had atrophic macular lesions and 22 (20%) had Group 2 and 3 changes. There was no correlation between the presence and type of macular lesions and patient age or genetic type of retinitis pigmentosa. Pruett27S observed similar findings in 383 eyes. 10. Optic Nerve Optic nerve pallor observed in patients with all types of retinitis pigmentosa does not indicate optic atrophy in the usual sense, since the retinal ganglion cells and nerve fiber layer remain intact until the late stages of the disease.“” In an ultrastructural study, Szamie? identified a thick preretinal membrane centered on the disc that extended over the retina in all quadrants. The preretinal membrane appeared to originate from fibrous astroglial cells in

Fig. 5. Top: Cystic-appearing macula in moderately advanced retinitis pigmentosa. Bottom: Late fluorescein angiogram demonstrates prominent fluorescein staining of cystoid spaces in the macula.

PAGON the optic nerve and was in direct continuity with and indistinguishable from Elschnig’s layer, the thin cellular membrane that lies on the surface of the optic disc. Szamier postulated that the reorganization of fibrous astrocytes in the optic nerve and migration of fibrous astrocytes into the thickened preretinal membrane over the optic nerve could contribute to the appearance of waxy pallor of the disc. The association of hyaline bodies of the optic nerve head with retinitis pigmentosa is well documented. These lesions may be unilateral or bilateral and have been observed in patients with Usher syndrome (Type I),19~zR1(Case ‘I simplex retinitis pigmentosa,?‘j autosomal dominant retinitis pigmentosa,2”3’“a’c “and X-linked retinitis pigmentosa.12” It is estimated that 2% of patients with retinitis pigmentosa would have disc druseni3” and there is no evidence that retinitis pigmentosa patients with such optic nerve lesions have a systemic disorder such as tuberous sclerosis.254 In patients with retinitis pigmentosa, in whom the diagnosis is not yet established, these optic nerve lesions may occasionally be misinterpreted as papilledema.lh7 These hyaline bodies have the appearance of either drusen or astrocytic hamartomas (Fig. 6).“’ Drusen of the optic nerve head are laminated, acellular, calcified concretions in the anterior lamina retinalis, frequently encircled by nerve fibers and glial cells.3oQAstrocytic hamartomas are a proliferation of glial cells that may be partially calcified and may be located in the retina or optic nerve. The juxtapapillary location of these lesions within the nerve fiber layer in retinitis pigmentosa patients has been considered diagnostic of astrocytic hamartomas, although histologic confirmation is lackHistologic examination of a lesion from one ing. Y68~283

Fig. 6. Hyaline

an astrocytic syndrome.

bodies of the optic nerve resembling hamartoma in a patient with Usher

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PIGMENTOSA

retinitis pigmentosa drusen.‘:’

patient

had the appearance

of

11. Symmetry Symmetry of retinal involvement is a recognized feature of all the types of retinitis pigmentosa.” Recently Massof et al’“’ examined 60 typical retinitis pigmentosa patients and observed a high degree of interocular congruence in the pattern of kinetic visual field defects and absolute threshold profiles as well as in abnormalities of color discrimination and visual acuity. B. UNUSUAL

FINDINGS

1. Sector Retinitis

OF SIGNIFICANCE

Pigmentosa

Sector retinitis pigmentosa is a term used to describe bilateral ocular involvement with sectoral changes in one quadrant or one half of each fundus. In some families there appears to be a distinct autosomal dominant condition in which all individuals with retinitis pigmentosa have sectoral involvement.“” Sectoral changes have also been seen on occasion in individuals with a family history of typical retinitis pigmentosa (most commonly of the autosomal dominant type) and in females heterozygous for the X-linked recessive retinitis pigmentosa gene.?“’ The incidence of sectoral changes in retinitis pigmentosa appears to be low, either because they are uncommon or because they are infrequently diagnosed due to the lack of characteristic symptonis:‘~ Clinical findings include: 1) retinal changes involving any quadrant or sector ofthe retina. Most commonly, the inferonasal quadrants are symmetrically involved;““I.UZH 2) abnormalities on fluorescein angiography which usually correspond to the observable areas of retinal abnormality but may be more widespread;“” 3) visual field defects less severe than those of typical retinitis pigmentosa and corresponding to the ophthalmoscopically abnormal retina.“O’ The held defects may be subtle and detected only with use of smaller test objects, or may be larger than the area of ophthalmoscopic involvement. Rarely the field defects of sector retinitis pigmentosa may be misinterpreted as being secondary to a neurologic problem; however, the visual field defects of retinitis pigmentosa have a disregard for horizontal and vertical meridians;‘“: 4) absence of symptoms of defective dark adaptation, despite widespread abnormalities of‘ rod and cone function detected by dark adaptometry,““’ EOG and ERG,‘;“” and vision threshold profile.‘~” There is conflicting information about the natural historv. of retinitis pigmentosa where sectoral

changes are present. Some investigators suggest that it is minimally progressive based on ERG findings,“’ but otherslbN have observed clinical progression or postulated that progression occurs in the ophthalmoscopically abnormal area.‘?” Krill et al”” noted no progression in a female heterozygous for X-linked retinitis pigmentosa, who had sectoral type changes. 2. Retinitis Pigmentosa Vasculopathy

With Exudative

A rare occurrence in patients with advanced retinitis pigmentosa in exudative vasculopathy, It is usually bilateral and shows no sex predilection.“” The fundus findings are telangiectatic vascular anomalies, serous retinal detachment and lipid deposition in the retinal periphery, often multifocal (Fig. 7). Pruett”” found 19 of 383 retinitis pigmentosa eyes (5%) to have abnormal vascular formations usually at the equator or in the peripheral fundus. Secondary serous detachment was seen in 8 of the 19. The cause of exudative vasculopathy in retinitis pigmentosa is unknown and multiple etiologies have been proposed. Angiographic and histologic findings in one case suggested choroidal neovascularization secondary to numerous breaks in Bruch’s membrane and not the unmasking of congenital vascular anomalies of the retina.“” The relationship between this exudative vasculopathy and the diffuse generalized permeability of retinal capillaries to fluorescein found in all genetic types of retinitis pigmentosa is not known.“‘.‘“” PruettY” postulated that minute but chronic retinovascular leakage could result in clinically undetected flat serous retinal detachments, relative hypoxia of the inferior retina, and consequent vascular changes.

Fig. 7. Telangiectatic retinal vessels with subretinal lipid deposition (arrows) in a patient with advanced retinitis pigmentosa and exudative vasculopathy.

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33(3) November-December

This vasculopathy is distinct from Coats’ disease, which is usually unilateral, nonhereditary, of childhood onset, and more common in males.‘Q2d Coats’ disease is characterized by telangiectasias and aneurysmal dilatations of the retinal vasculature that cause exudation and lipid deposition in the retina. It has been suggested that the designation Coats’ disease should be reserved for those classic cases, and the term “retinal vasculopathy of the Coats’ type” should refer to an atypical exudative as that seen in retinitis vasculopathy such Familial occurrence of typical retpigmentosa.‘26 initis pigmentosa and exudative vasculopathy is reported but rare.s”6 3. Unilateral

Retinitis

PAGON

1988

Pigmentosa

Unilateral retinitis pigmentosa is a misnomer and describes a condition more appropriately termed unilateral retinal pigmentary degeneration. A brief discussion is included here for completeness. Patients with unilateral retinal pigmentary degeneration have functional and ophthalmoscopic changes in the affected eye that are typical of retinitis pigmentosa; however, in the fellow eye these are no symptoms and the ERG remains normal, even when observed over time.‘>* Fransois’“” and Carr and Siegel74 proposed that the late onset and lack of hereditary factors make unilateral retinal pigmentary degeneration pathogenetically distinct from retinitis pigmentosa. The cause is usually not known, but a number of conditions have been documented, including transient ophthalmic artery occlusion,74 perforating injury to the eye without direct trauma to the retina,22,85 and structural defects such as pit of the optic disc in which there is longstanding serous While syphilis has traditionretinal detachment.14’ ally been considered in the differential diagnosis, luetic retinitis is often bilateral and associated with good visual acuity and preserved (although not necessarily normal) rod and cone responses on ERG.S04

of millions of retinal cells. The ERG is detectable all around the eye and for clinical purposes can be measured most successfully with a double electrode contact lens placed on the cornea, the output of which is amplified and displayed on an oscilloscope. Rod responses can be separated from cone responses, which permits definition of the type and extent ofrod and/or cone involvement in the various retinal dystrophies. This separation is accomplished by varying the wavelength of the stimulus, the state of retinal adaptation to light and dark, and the frequency with which the stimulus is presented.‘j” Pure rod-mediated responses can be elicited from a retina dark-adapted for 30-45 minutes with a

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C. TESTS OF VISUAL FUNCTION 1. Electroretinography The electroretinogram (ERG) is invaluable in the documentation of early loss of photoreceptor function, may provide prognostic information in some cases of retinitis pigmentosa, and is potentially useful in evaluating therapeutic modalities for retinal dystrophies. It should be performed on all patients in whom the diagnosis of retinitis pigmentosa is in question. The ERG is an electrical potential which arises in the retina after light stimulation and represents a composite response

Fig. 8. Three superimposed single trace cornea1 ERGS of normal, dark adapted 26-year-old woman. l-3: responses to full field, dim, suprathreshold, scotopically matched blue (h < 470 nm), and red (h > 600 nm) flashes, and to white (16 ft-L) flashes, respectively. 4: responses to full field 30HZ white flicker (16 ft-L) in the absence of background light. 5-7: ERGS to white (16 ft-L), and to photopically matched yellowred (h > 550 nm) and blue green (A < 550 nm) flashes, respectively, in the presence of background light (10 ft-L). (Figure and legend reprinted from Chatrian G E et al: Am J EEG Technol20:57-77, 1980, with permission of the author and publishers.)

RETINITIS

PIGMENTOSA

single flash blue (less than 470 nm) light stimulus (Fig. 8:l). A single red (greater than 600 nm) stimulus produces a duplex response with both cone and rod components (Fig. 8:2), as does a white light flash on the dark-adapted retina (Fig. 8:3). Cone responses are elicited with either a white or red light flickering at 30 cycles per second (Fig. 8:4), or a single white flash (Fig. 8:5) or yellow-red (Fig. 8:6) or blue-green (Fig. 8:7) stimulus in the lightadapted stage.‘H.“’ Ii” The components of the ERG are the a-wave, b-wave, and c-wave (Fig. 9). The cone or rod response has an initial cornea-negative component, the a-wave, which appears to arise in the photoreceptor layer. This is followed by a cornea-positive b-wave which appears to arise from the inner nuclear layer of the retina (i.e., the horizontal, bipolar, amacrine and Miiller cells). The c-wave originates in the pigment epithelium and is not utilized clinically. The ganglion cell layer and nerve fiber layer do not play a role in the ERG.‘“” Most ERG laboratories utilize a ganzfeld system which allows for full-field homogeneous illumination of the entire retina.Z’” Many factors influence the ERG response, such as the intensity and wavelength of the stimulus, full-field versus focal stimulation of the retina, the rate at which the light stimulus is presented to the retina, the state of dark adaptation of the retina and the age, sex and refractive error of the subject. Laboratories performing ERGS may control these variables in a different manner such that data from one laboratory is not necessarily directly comparable to that generated in another laboratory.‘in The parameters most commonly measured in the ERG are the a- and b-wave amplitude and implicit time. The b-wave amplitude is measured from the a-wave trough to the b-wave peak. The b-wave implicit time is the time elapsed from the onset of the stimulus to the major cornea-positive peak of’ the wave. Recent advances in technology, such as quantitative computer analysis of a- and b-wave parameters has permitted identification of very low voltage abnormal responses.“‘,“,‘“.‘” Patients with advanced retinitis pigmentosa have nondetectable rod and cone responses. In patients with early disease the a- and b-waves generated by the photoreceptors in response to white light under reduced in conditions are dark-adapted amplitude.‘” Similarly, in all genetic subtypes of retinitis pigmentosa, the pure rod responses have b-wave amplitudes which are nondetectable or reduced with either prolonged implicit times”’ ?‘I or normal implicit times.“’ This early and severe impairment of pure rod responses in all genetic forms ofretinitis pigmentosa makes the assessment

of rod responses invaluable in the detection of early retinitis pigmentosa. The determination of rodmediated responses by ERG is critical in the diagnosis of young patients suspected of having any type of retinitis pigmentosa or known to be at risk by family history, since diagnostic ERG abnormalities have been detected in children as young as six years old.“” The separation of the rod and cone responses of patients in the early stages of retinitis pigmentosa may help to distinguish progressive forms from self-limited forms.“‘,“” Marmor”’ determined from a review of ERG findings in 70 consecutive patients with retinitis pigmentosa that individuals with normal cone b-wave implicit times were found within every hereditary type of retinitis pigmentosa. Such a finding therefore did not allow for classification of patients by genetic type, but did identify a subgroup (12170 or 17%) of retinitis pigmentosa patients with a more favorable visual prognosis. In his laboratory these individuals had a flicker b-wave implicit time

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Fig. 9. Single trace cornea1 ERG elicited by a flash of white light in normal dark adapted human subject. Brief transient with onset at time 0 is flash artifact and upward deflection signifies cornea1 positivity. (Figure and legend reprinted from Chatrian G E et al: Am] EEG Technol Z&57-77, 1980, with permission of the author and publisher.)

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within the normal range (less than or equal to 32 msec) and a mixed rod and cone b-wave amplitude greater than 100 microvolts. It is not clear how age or progression of retinal degeneration alter the ERG responses in this group. Patients with sectoral changes of retinitis pigmentosa have also been noted to have favorable ERG findings. Reduced rod and cone b-wave amplitudes with normal rod and cone b-wave implicit times were reported by Berson and Howard.“7 Using conventional electroretinography, the majority of patients with newly diagnosed retinitis pigmentosa had nondetectable ERGS, often defined as less than 10 microvolts.4’~‘20 Pruett found the ERG undetectable in 7 1% of 307 eyes from 192 patients.274 In a more recent study, of 94 selected patients in which computer averaging was utilized, Berson et al determined that full field ERGS to single flashes of white light were less than 10 microvolts in 60%, and nondetectable (less than 1.0 microvolt) in 22%.“’ When all full-field ERG test conditions were considered, only nine of these 94 patients (10%) had no detectable responses. The ERG is not correlated with the visual acuity of retinitis pigmentosa patients whether one considers data from studies utilizing conventional ERGsZ2’ or newer techniques.4’ Although Marmor found that patients with recordable signals were more likely to have better acuity than those with nonrecordable signals, about half of patients with nonrecordable ERGS had an acuity of 20/40 or better.221 There may be little correlation between rod-mediated responses on ERG testing and the final dark adaptation threshold as measured by a Goldmann-Weekers adaptometer, since the latter procedure measures a focal retinal response (11” above the fovea) whereas the ERG is a full-field testZ2’ It has been debated whether the ERG findings are helpful in determining the genetic subtype of retinitis pigmentosa3’~22’ and no correlation between specific ERG findings and genetic subtype has been found. Monitoring of clinical therapeutic trials was hampered by the limitations of conventional ERG testing in which the majority of retinitis pigmentosa patients had nonrecordable responses, suggesting that the population with preserved responses either had atypical diseasez2’ or necessarily were young.28 The ability to detect low voltage responses in a greater portion of retinitis pigmentosa patients should expand the use of the ERG in monitoring intervention strategies by permitting the inclusion of patients with more advanced disease.41 The electroretinogram is invaluable in the evaluation of individuals at risk to inherit one of the forms ofretinitis pigmentosa. Berson has suggested

PAGON

that individuals at risk for retinitis pigmentosa who have normal ERGS at less than 20 years of age will not develop retinitis pigmentosa latereZg 2. Dark Adaptation

and Visual Sensitivity

Visual threshold refers to the minimum intensity of light that will stimulate the rods or the cones to elicit a subjective response. To measure visual sensitivity, a test light positioned on a given area of the retina is dimmed to a subthreshold level and then made gradually brighter until it is perceived by the subject. The intensity at which it is perceived is defined as the visual threshold, threshold intensity, or absolute threshold, and may be expressed in log units. Vistual sensitivity is the inverse of the threshold intensity, also expressed in log units. Dark adaptation involves the measurement of the absolute threshold at given time intervals as the retina adapts to the dark. The Goldmann-Weekers adaptometer is most commonly used and unless modified, tests only one retinal area. The patient is exposed to preadapting white light after which absolute thresholds for white light are measured at intervals for 40 minutes until a final darkadaptation threshold is obtained. This final rod threshold, expressed in log units, is a sensitive index of rod function.2”“.s4’ If electroretinography is available, measurement of dark adaptation may not offer additional information for the diagnosis or management of a given patient. Massof and Finkelstein2~7~22gexamined rod sensitivity relative to cone sensitivity in any portion ofthe retina by utilizing a red stimulus (650 nm) and a blue-green stimulus (500 nm) and calculating darkadapted threshold differences for the two stimuli. With their technique, the patient is dark-adapted for 40 minutes and an Oculus Tubingen perimeter is used to position a 2” light stimulus anywhere in the visual field. Fifteen patients with typical retinitis pigmentosa and relatively preserved visual fields were classified solely by threshold pattern into Type 1 characterized by early and diffuse loss of rod function with later, regionalized progressive loss of cone function, and Type 2 characterized by regionalized and combined loss of rod and cone function.226~227~230 From comparison of early and advanced cases, they concluded that one type does not evolve into the other and they appear to represent different disease processes. Whether Type 1 and Type 2 patients reflect true genetic heterogeneity is not clear since both types were present in a large study of autosomal dominant retinitis pigmentosa”’ as well as in simplex cases,226 although these types have also been observed to run true in families. While the technique of Massof and Finkelstein is not utilized routinely in clinical diagnosis and manage-

RETINITIS PIGMENTOSA ment, it is of research interest since it may allow for detection of rod function even when rod ERGS are not detectable. 3. Visual Field AI1 patients with retinitis pigmentosa and many suspected of having retinitis pigmentosa require visual field testing. Kinetic visual field testing using a Goldmann bowl perimeter has become the modern clinical standard. In this technique test objects, ellipses of light, varying in size from l/16 mm’ to 64 mm’ and designated by Roman numerals from 0 to V are projected upon and moved through a uniformly illuminated background. Luminosity of the test objects is expressed as arabic numerals from 1 to 4 and lower case letters from a to e; hence, the largest brightest test object is Vi4e. Static perimetry is performed in the same manner as visual sensitivity except that the background is illuminated in the mesopic-photopic range. It is the method utilized by most computerized perimeters and is being used with increasing frequency, Tangent screens limit the examination to within 30”of fixation and hence are not useful in the evaluation of the patient with early retinitis pigmentosa. Symptomatic defective dark adaptation in patients with retinitis pigmentosa is accompanied by peripheral field restriction. The characteristic ring scotoma in the midperiphery of the visual field usually starts as a group of isolated scotomas in the area 20 to 25 degrees from fixation (Fig. 10). These gradually coalesce to form a partial and then a complete ring (Fig. 11). The outer edge of the ring expands fairly rapidly to the periphery, while the inner margin contracts slowly toward fixation (Fig. 12). Long after the entire peripheral field is gone,

147 there remains a small oval of intact central field (Fig. 13).‘hl’ There are few published studies on the rate of visual field loss in patients with retinitis pigment0sa.l’ In a series of 104 patients with autosomal dominant retinitis pigmentosa, 93%’ of patients under age 20, 89% of those from 20-40, and 60% over the age of 40 had a central visual field radius of 10” or greater with the IV/4 test object.“’ However, Ross et aP” noted marked interexaminer and intervisit variability of visual fields as measured by kinetic perimetry in patients with all types of retinitis pigmentosa, even under rigidly controlled test conditions. Such variability may be due to differences in test conditions (e.g., pupil size, increasing dark adaptation during a testing session and instrument calibration) or different techniques of the examiner or patient conditions (e.g., fatigue, increasing experience with the test or fluctuations in retinal sensitivity). More accurate measurement of visual fields will enhance the study of the natural history of visual field loss in patients with retinitis pigmentosa.‘“” Retinitis pigmentosa patients may qualify as legally blind by visual field criteria before visual acuity drops to the level established for legal blindness. Hence, visual field testing is useful not only for diagnosing retinitis pigmentosa, but also for determining legal blindness. 4. Fundus Reflectometry Fundus reflectometry is a useful research technique for quantitative assessment of photopigment regeneration. It has found limited clinical use to date? The reduction of light sensitivity in rods demonstrated by this technique suggests reduced

Fig. 10. Visual field of left eye (left) and right eye (right) of a 1%year-old girl with autosomal dominant pigmentosa using III4e test object demonstrating the isolated scotomas in the midperiphery characteristic retinitis pigmentosa.

retinitis of early

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33(3) November-December

1988

PAGON

Fig. 1 I. Visual field of left eye (left) and right eye (right) of a 29-year-old woman with autosomal pigmentosa using V4e test object demonstrating a midperipheral ring scotoma.

rhodopsin content within the areas of abnormal retina because of an abnormally low amount of pigment in the photoreceptors, perhaps secondary to shortening of the outer segments’g’,““” or to a partial, or mosaic, loss of rods.‘g’

5. Contrast

Sensitivity

Contrast sensitivity testing involves the use of standardized sinusoidal black and white gratings of varying density to detect abnormalities of macular function. It is a more sensitive measure of macular function than standard visual acuity testing of discrimination of small objects of high contrast. While poor contrast sensitivity has been detected in retinitis pigmentosa patients with normal visual acuity, the significance of this finding in terms of differentiating it from other retinal disorders and

recessive retinitis

correlating with clinical severity or genetic subtype is not known.180.ZO6.223 6. The Electrooculogram The electrooculogram (EOG) utilizes cutaneous electrodes placed at the medial and lateral canthi to record the standing potential between the cornea and the posterior pole of the eye, also called the cornea-retinal potential. The EOG is thought to measure a function of both the pigment epithelium and photoreceptors.” The EOG is expressed as the ratio of the amplitude of the first light peak (maximum response obtained during retinal illumination) to the amplitude of the dark trough (a basal level during reduced illumination). Although the EOG is usually abnormal in retinitis pigmentosa even in early stages, the electroretinogram is viewed as a more sensitive and reliable index of photore-

Fig. 12. Visual field ofleft eye (left) and right eye (right) ofa 49-year-old woman with autosomal dominant retinitis pigmentosa using V4e test object showing extension of the midperipheral scotoma to the periphery.

RETINITIS PIGMENTOSA

l-19

ceptor function and hence, is the preferred trophysiologic method of diagnosis.200 7. The Visually

elec-

Evoked Response

The visually evoked response (VER) refers to an electrical response from the visual cortex following a flash of light or pattern stimulus in front of the eye. The cellular basis of the VER is not totally understood, but at the retinal level is believed to be primarily a function of macular and fovea1 cones.?“” The VER has not been helpful in the diagnosis or monitoring of photoreceptor deterioration of patients in any stage of typical retinitis pigmentosa. 8. Fluorescein

Angiography

Fluorescein angiography may be of value in documenting early deterioration of the retinal pigment epithelium in all patients with retinitis pigmentosa and especially in female carriers of X-linked retinitis pigmentosa. It has a role in the evaluation of patients with exudative vasculopathy and cvstoid macular edema. 9. Vitreous

Fluorophotometry

Vitreous fluorophotometry is a method of evaluating the blood-retinal barrier by quantifying the leakage of fluorescein from retinal vessels into the posterior vitreous. Patients with severe retinal involvement from retinitis pigmentosa regardless of genetic type have marked elevations of dye concentration in the vitreous.“’ Vitreous fluorophotometry is not widely available clinically, but may be useful in detecting an abnormality of the bloodretinal barrier in patients with otherwise normal retinal appearance and function, such as female carriers of X-linked retinitis pigmentosa.“y

Fig.

13. Visual fields of 39-year-old of 18” diameter.

D. CLINICAL EVALUATION OF PATIENTS 1. Family History

Since the family history is the only means of determining the specific genetic subtype of retinitis pigmentosa in a given patient, a three generation pedigree should be obtained on all patients with special attention to consanguinity, ethnic origin, maternal male relatives and other close relatives. Often ophthalmologic evaluation of other relatives can clarify the mode ofinheritance in a given patient (see Section IV). All patients, even those with typical ophthalmologic findings of retinitis pigmentosa and a well-documented family history of retinitis pigmentosa, should have an assessment of visual fields and an ERG, to determine if the observed changes in photoreceptor function provide prognostic information. 2. Medical

History

Past medical history and review of systems should be thoroughly explored in order to determine if the retinitis pigmentosa is an isolated ocular condition or a manifestation of a systemic disorder. Patients with other medical problems, including hearing loss, warrant further evaluation for the systemic disorders associated with retinitis pigmentosa (Section V). Since most of these disorders are autosomal recessive, patients with a “negative” family history are still at risk for having one of these conditions. 3. Laboratory

Testing

Laboratory testing that can be helpful in distinguishing retinitis pigmentosa from other ocular disorders are serologic tests for syphilis, serum ornithinelysine ratio, and serum phytanic acid level.

man with type I Usher syndrome

using V4e test object showing

central

field

150

Surv Ophthalmol 33(3) November-December 1988

PAGON

14. Gyrate atrophy of the choroid and retina. Note the scalloped defects of the pigment epithelium and choroid. This patient (#5 in the series of Weleber et al 1982) did not respond to pyridoxine therapy. (Photo courtesy of Richard G. Weleber, M.D.)

Fig.

II. Differential Diagnosis A. GENETIC DISORDERS THAT CAUSE RETINAL DEGENERATION 1. Gyrate Atrophy

of Choroid

and Retina

Gyrate atrophy of the choroid and retina, a rare autosomal recessive disorder that is more common among people of Finnish origin, presents with symptoms of defective dark adaptation and restricted visual fields, but can be distinguished from retinitis pigmentosa by the appearance of the fundus and by appropriate laboratory tests. Early in the disease, circumscribed, discrete round patches of choroidal and retinal atrophy occur in the midperiphery. As the disease progresses these areas coalesce to form the sharply defined, scalloped defects of the pigment epithelium and choroid to which the term “gyrate” has been assigned (Fig. 14). Retinal vessels become attenuated over time and the discs become atrophic.S’g-S2’ Detection of a ten to twenty-fold evaluation of plasma ornithine levels by Simell and Takki in 1973502 led to the discovery of deficient ornithine-ketoacid aminotransferase in cultured skin fibroblasts from homozygotes.260~S2S~52~ Therapy has been attempted with pyridoxine (vitamin B6)332and/or low protein diet36.326and creatinine supplement.sos Variable biochemical responsiveness to vitamin B, therapy suggests genetic heterogeneity.36.‘*5,554It is not yet clear whether any of these therapies alter the natural history of the retinal degeneration.J6 Prenatal diagnosis is possible using cultured amniocytes. Generalized manifestations include muscle weakness, abnor-

mal EMG, EEG, and atrophy ofType II muscle fibers. Patients with retinitis pigmentosa have normal plasma levels of ornithine.‘* 2. Choroideremia Choroideremia is an X-linked recessive disorder in which initial symptoms are defective dark adaptation and restricted visual fields.‘*’ Although the fundus appearance in late stages is distinctive, the early stage consists of fine pigmentary stippling and atrophy of the posterior pole and mid-periphery of the fundus. In later stages, patchy areas of retinal pigment epithelial and choroidal atrophy appear in the midperiphery and gradually coalesce into pale, yellow confluent areas (Fig. 15A). As in retinitis pigmentosa, there is relative sparing of the macula, even in moderately advanced cases (Fig. 15B). The retinal vessels are relatively preserved even in advanced cases, in contrast to retinitis pigmentosa and gyrate atrophy of the choroid. Carrier women generally have pigmentary stippling and atrophy in the fundus periphery but may have more central involvement or more peripheral atrophic changes. Progression of these lesions is typical. Carriers may be misdiagnosed as having “atypical retinitis pigmentosa.“soj Recent molecular genetic studies have localized the choroidermia gene to the long arm of the X chromosome between bands q13 and q21 .po5 3. Cone-Rod

Dystrophy

Cone-rod dystrophy, also known in the past as inverse or central retinitis pigmentosa, is char-

RETINITIS PIGMENTOSA

Fig. 15. Left: Moderately advanced choroideremia with diffuse retinal pigment epithelial and choroidal loss. Right: Advanced chorideremia with islands of retinal pigment epithelium and choriocapillaris preserved in the macula and peripapillary area.

acterized

by

bilateral

and symmetric loss of cone function in the presence of reduced rod function.‘(” In this disorder, loss ofcentral visual acuity, photoaversion and color vision defects appear before peripheral visual loss and defective dark adaptation. Cone-rod dystrophies tend to have early onset such that there may be vision deprivation nystagmus and marked visual impairment by age 20 to 40 years. The fundus changes may at times be confused with those of retinitis pigmentosa. Cone-rod dystrophies may be an isolated ophthalmologic disorder or may be part of a systemic disorder, some of which are reviewed in Section V. In fact, the retinal dystrophy of systemic disorders is often a cone-rod dystrophy, rather than typical retinitis pigmentosa. Whether cone-rod dystrophy is an ocular disorder or part of a systemic disorder, alltosomal recessive inheritance appears to be more common.

4. Cone Dystrophy Cone dystrophy refers to those retinal dystrophies in which there is marked abnormality in cone The function with some’*’ or no”” rod involvement. mode of inheritance is usually autosomal dominant. The age of onset is variable, but most commonly before the age of 20 years. The retinal appearance is characterized by a bull’s eye macular atrophy which is strikingly apparent on fluorescein angiography (Fig. 16). Few or no peripheral retinal changes may be seen despite marked central visual loss. There appears to be both inter- and imrafamilial variability in the severity of disease, rate of progression and degree of rod involvement?“” The ERG shows marked abnormality in cone function and variable rod involvement.““’ The visual field shows a central scotoma and, in some cases, peripheral field restriction.

Fig. 16. Left: Posterior fundus of a patient with cone dystrophy. The macula and parafoveal epithelium appear atrophic. Right: Fluorescein angiography shows distinct bull’s_eye macular transmission hyperfluorescence through defective retinal pigment epithelium.

retinal pigment lesion caused by

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Surv Ophthalmol 33(3) November-December 1988

An X-linked form has recently been described in which patients may not be symptomatic until their late 20s or early 3Os, but have a peculiar tapetal-like sheen of the retina and abnormal cone responses on ERG testing from an early age.lG6 5. Leber’s Congenital Amaurosis Onset Retinitis Pigmentosa

and Early

Leber’s congenital amaurosis is a heterogeneous group of inherited retinal disorders of childhood which may occur as an isolated retinal dystrophy or as part of a systemic disorder.‘28 The study of Foxman et aliz begins to sort out this heterogeneous group by classifying patients according to age of onset of visual loss, severity of loss of visual acuity and visual fields, and presence or absence of nonocular abnormalities. Fundus appearance alone was not useful in classifying patients. In a retrospective study of 36 patients, Foxman et al”” included only those patients who had a complete ophthalmologic evaluation and ERG testing before the age of ten years. Of the four classifications proposed by them, only Group 1 and possibly Group 3 represent distinct clinical entities. Group 1 termed “uncomplicated Leber’s congenital amaurosis” includes patients with congenital blindness, searching nystagmus, and nondetectable ERG responses. All 16 children in this group had hyperopia, ranging between +4.00 and + 10.50 D on initial presentation, a finding which the authors feel might eventually prove to be useful in classifying patients. Two had bilateral macular colobomas and none had keratoconus. None had any systemic involvement. Autosomal recessive inheritance appeared likely in the three familial cases (from two families). Group 2 included patients with ophthalmologic findings similar to Group 1 plus systemic involvement, including some of the disorders described in Section V of this paper, as well as undiagnosed neurologic conditions. Group 3 patients, termed ‘Ijuvenile retinitis pigmentosa,” had visual impairment after the age of 6 months but before 2 years with reduced visual acuity (to the range of 20/80 or better), constricted visual fields and nondetectable or markedly reduced ERG responses. None were familial cases and none had neurologic involvement. The 10 patients in Group 4 were classified as “early onset adult retinitis pigmentosa.” Defective dark adaptation was noted at about age 6 years and all had markedly abnormal ERG responses but reasonably well preserved central vision (20/50). The heterogeneous nature ofthis group (e.g., two patients with hearing loss, one with consanguineous parents and one with an affected mother) suggests that these patients represent the full spectrum of typical retinitis pigmentosa and do

PAGON not represent patients.

a clearly

6. Congenital

Stationary

distinguishable

subset of

Nightblindness

This includes congenital stationary nightblindness (CSNB) with normal fundi, which can be either an autosomal dominant or recessive disorder or an X-linked recessive disorder with myopia. Based on results of fundus reflectometry, electroretinography and other tests, Carr72 concluded that these forms of CSNB were probably due to defects in neural transmission and not defects in rhodopsin metabolism. The two forms of CSNB with abnormal fundi, Oguchi’s disease and fundus albipunctatus, are autosomal recessive disorders in which the rod thresholds return to normal or improve appreciably after dark adaptation for several hours. In Oguchi’s disease, the fundus has a peculiar gray-white discoloration when exposed to the light that disappears after prolonged dark adaptation (Mizuo-Nakamura phenomenon). The pathogenesis appears to be a defect in neural transmission. In fundus albipunctus there are numerous yellow-white spots located deep in the retina which extend from the posterior pole where they are the most dense to the periphery. The macula is spared. This disorder, caused by a defect in rhodopsin regeneration, is physiologically distinct from the retinal dystrophies. Although it has been considered ophthalmoscopically similar to “retinitis punctata albescens,” fundus albipunctatus does not have the funduscopic changes of diffuse retinal atrophy, attenuated vessels, disc pallor and black While fundus albipunctatus is a pigment c1umps.72~Z20 distinct autosomal recessive condition, the pathogenesis of retinitis punctata albescens and its relationship to other retinal degenerations is unc1ear.j Some believe it to be a manifestations of retinitis pigmentosa and not a separate entity.3j B. DRUG EXPOSURE (MELLARIL)

- THORIDAZINE

CHORIORETINOPATHY

Thioridazine hydrochloride (Mellaril) in high doses causes a pigmentary retinopathy and atrophy of the choriocapillaris. The retinopathy initially presents in the posterior pole with a pigmentary mottling or stippling which may progress through an intermediate nummular stage (Fig. 17) followed by coalescence into plaquelike pigment clumps of uniform size, overlying areas of retinal pigment epithelial atrophy. Patients complain of defective dark adaptation and occasionally blurry vision; visual field testing may reveal a ring scotoma; and ERG responses may be normal in the early stages, but become markedly abnormal during later stages.‘14 Toxicity is thought to be dose-related.“4 After discontinuation of the drug the pigmentary retinopathy

RETINITIS

1%

PIGMENTOSA clumping in the macula (Fig. 1X) and/or dust-like stippled pigment changes in the periphery.

ot

III. Prevalence of Retinitis Pigmentosa

17. Nummular areas of retinal pigment epithedial and choriocapillaris atrophy and large pigment aggregates in Thioridazine (Mellaril) chorioretinopathy.

Fig.

and abnormalities of retinal function may resolve, stabilize, or progress; progressive changes may occur in the retina and choriocapillaris years after discontinuation of the drug.Y”7 Mellaril is adsorbed by melanin granules and it has been postulated that an inhibition of oxidative phosphorylation within the photoreceptors, pigment epithelial cells, or both causes the chorioretinopathy.““:Z’7 C. INFECTIONS 1. Syphilitic

Neuroretinitis

Patients in the early stages of secondary or latent syphilis may develop unilateral or bilateral visual loss associated with inflammatory retinal edema (retinitis), optic disc swelling (papillitis) or both (neuroretinitis).‘5,‘Zi Such patients will have positive specific anti-treponemal antibody tests (such as FTA-ABS or MHA-Tp). Following appropriate treatment visual acuity usually returns to normal. Generally, disc changes and residual pigmentary mottling of the fundus. often in the macula, are the only ophthalmoscopic signs after the inflammatory process resolves. The EKG may be normal”“‘or show reduced a- and b-wave amplitudes, but normal implicit times.?“!’ Paracentral scotomas, arcuate defects and mild contraction of the isopters may be present during the acute phase but peripheral visual field defects are llnusual.

In a recent study in the L’nited States the overall incidence of retinitis pigmentosa was indirectly claculated to be about 113700, based on 670 probands from 648 families from a voluntary registry of a lay organization.ik In a prospective study in the state of Maine extending over foul years, 1X5 subjects were evaluated.“’ The prevalence of retinitis pigmentosa was estimated to be 1 in 4756; excluding LJsher syndrome and BardetBiedl syndromes the prevalence kvas 1 in 5 193. The estimated birth incidence of persons who would become affected with nonsyndromic retinitis pigmentosa was 1 in 3544. -The incidence of newly diagnosed cases per year ~vas about 6 per I .OOO,OOO population.“’ In a study of all symptomatic cases of’ retinitis pigmentosa and “cone dystrophy” in Birmingham, England, in 1978, 15 1 index cases horn 144 families and an additional 63 affected relatives were ascertained. I’he prevalence for all ages calculated to be 1 in 4869 and for the age group -15 to 64 years was 1 in 3195.“” In this study, 70% of ascertained cases had been diagnosed by age 30 years. 78% by age 40 years, 86% by age 50 years, and IOW 1)). 70 years. Therefore, the latter prevalence figure of I in 3 195 may be more representative of the birth frequency of persons destined to develop any of‘ the genetic subtypes ofisolated retinitis pigmentosa, syndromic retinitis pigmentosa, and cone dvstrophv during their lifetime. These prevalence figures are comparable to the estimates of 1 in 7OO(j in Switzerland.”

2. Rubella Rubella ret.inopathy is a sequelum of congenital rubella and is characterized by pigmentary retinopathy, normal retinal vessels, and normal retinal function as assessed by visual acuity, visual fields, dark adaptation, color vision and electroretinography.‘““The pigmentarv changes include pigment

18. Mild pigment alterations in the macula of’ a patient with congenital rubella syndrome. Note normal optic disc and retinal vessels. L’isual filnction is normal.

Fig.

154

Surv Ophthalmol

33(3) November-December

1988

1 in 4500 in Israel,255 1 in 4016 in China,‘75 and 1 in 4440 in Norway.‘53 Retinitis pigmentosa is said to be responsible for over 6% of the registered blind under the age of 65 years in England and Wales.‘03 In Canada retinitis pigmentosa ranked second only to diabetic retinopathy as a cause of visual impairment in the 16 to 50 year age group.262 In a survey of 486 visually handicapped children, Bryars and ArcherG determined that 13% of the partially sighted and 11% of the blind children had “tapeto-retinal dystrophies” (a classification that included hereditary macular degenerations).

PAGON

retinitis pigmentosa is observed in three generations of a family,59 whereas others have determined that two-generation involvement is sufficient because of the low penetrance of the autosomal dominant retinitis pigmentosa gene.65 In most series, the autosomal recessive group includes those patients with reportedly normal parents and multiple affected siblings or consanguinity.5g However, in at least one study6” mildly affected siblings (whose asymptomatic parents were not examined) were not classified as having autosomal recessive retinitis pigmentosa since the possibility of a mildly affected parent (and hence autosomal dominant inheritance) could not be excluded. X-linked recessive inheritance is assumed if there is a typical X-linked pedigree (more than one affected male related through carrier females), or if ophthalmologic or electrophysiologic testing detects a heterozygous female relative. “Simplex” cases are those in which there is no family history of affected individuals and no consanguinity. Any assessment of the frequency of the various genetic subtypes in a series needs to distinguish between the proportion of genetic subtypes in probands (or families) versus the proportion of genetic subtypes in affected individuals; otherwise bias is introduced into the analysis of the dominant and simplex proportions which are the most senof the various sitive to sampling error. 5g Incidence subtypes of retinitis pigmentosa varies between published surveys (Table 2) and may reflect differ-

IV. Genetics of Retinitis Pigmentosa As emphasized earlier, the term retinitis pigmentosa refers to a heterogeneous group of hereditary disorders in which there is progressive loss of photoreceptor and pigment epithelial function. Generalizations about the clinical course and ophthalmologic findings of patients with typical retinitis pigmentosa have been discussed previously. Patients diagnosed to have retinitis pigmentosa most commonly have an isolated disorder in which there are no systemic manifestations. Less commonly, retinitis pigmentosa occurs in disorders with systemic manifestations (Section V). When retinitis pigmentosa is part of a symptom complex, it may be possible to diagnose a specific syndrome of known genetic etiology and to provide accurate genetic counseling. When retinitis pigmentosa occurs in an isolated finding in an otherwise healthy individual, determination of the mode of inheritance (i.e., autosomal dominant, autosomal recessive, or X-linked recessive) is much more difficult and can only be made by the family history.‘g.“j.‘“” In order to discuss the genetics ofisolated retinitis pigmentosa, definitions of autosomal dominant, autosomal recessive and X-linked recessive need to be established: In some series autosomul dominant inheritance is inferred only when direct vertical transmission of

ences

in the method

ness of family studied. Boughman

of ascertainment,

studies,

thorough-

and age of the population

et al’” used

uted to a lay organization.

a questionnaire Difficulties

distrib-

in such a study

include lack of objective clinical documentation and inability to do family studies, as well as possible bias in the type of respondent related to age, severity of disease and socioeconomic status. Bundey and Crews64 point out that 44 of 251 patients (17.5%) ascertained by them as having retinitis pigmentosa

TABLE

2

Distribution of Genetic Types of Retinitis Pigmentosa by Proband Study Boughman Jay”’

& [email protected]

Bundey & Crew?

genetic clinic** electrodiagnostic laboratory**

AD

AR isolated

22% (65) 24%( 104)

16%(48) 7%(29)

15% (43) 22% (30)

1% (4) 10%(14)

AD - autosomal dominant; AR - autosomal recessive; ** indicates method of ascertainment.

AR syndrome

13%(18)

XLR

Uncertain

Simnlex

Total

9%(27) 16%(67)

3.3%(10) 11% (47)

50%(150) 41%(175)

300 426

70%(203) 37% (51)

289 138

4%(11) 14%(19)

XLR - X-linked recessive;

9%

simplex

(25) (5)

- see text for definition;

RETINITIS

PIGMENTOSA

were incorrectly diagnosed and, hence, cast doubt on the validity of data collected via questionnaires. Jay Ix>and Boughman and FishmanS ascertained patients through genetic, ophthalmologic, and subspecialty ophthalmologic clinics that serve as referral sources for retinitis pigmentosa patients; this may have excluded more mildly affected individuals and included more familial cases. Bundey and Crews”” and Bunker et al”’ evaluated a population of retinitis pigmentosa patients selected by geographic location alone in an attempt to avoid the biases inherent in the previous studies. It can be concluded that X-linked recessive retinitis pigmentosa is the least common form, comprising about 5- 15% of probands (Table 1). Autosomal dominant retinitis pigmentosa comprises 15-25% of probands, while documented autosomal recessive retinitis pigmentosa comprises about 5-20’15: of probands. The largest proportion (about 40-50s consists of simplex cases.“,“,““.“” X-linked dominant retinitis pigmentosa is extremely rare, with only one reported family.“‘” The high incidence of simplex retinitis pigmentosa cases has been confirmed in all series analyzing genetic subtypes. If simplex cases are included with autosvmal recessive cases, then the proportion of autosomal recessive cases may be as high as 85-W% ,” a proportion considered inordinately high in recent studies.i”,‘,i The higher incidence of recessive retinitis pigmentosa in prior studies may reflect bias of ascertainment for more severe cases (and hence more recessive cases) or a high incidence of consanguinity in certain populations. In contrast, Bundey and Crews’” conclude that recessive retinitis pigmentosa is extremely rare in England, since half of their patients with autosomal recessive retinitis pigmentosa had consanguineous parents. The fact that 40-50’S of patients with retinitis pigmentosa are simplex cases has perplexed geneticists who have invoked several tentative explanations. 1) Some simplex cases may be attributable to multifactorial etiology and environmental phenocopies.“‘.lHZ1 2) Others may be caused by a new mutation for an autosomal dominant gene;j”,“‘, however, new dominant mutations may be rare in view of the normal fertility in gene carriers.“’ 3) Penetrance of the autosomal dominant gene may be less than 10096, i.e., not all individuals who carry the gene manifest the disorder. Boughman and Fishman’” calculated that the penetrance for autosomal dominant retinitis pigmentosa may be as IOU as 40% after the age of 30 years, and that a substantial proportion of simplex cases (perhaps 75%) ma)’ be the offspring of’ minimally affected parents. I‘hereEore, ophthalmologic examination

15.5

and ERG testing of parents would be necessary to identify those families in which autosomal dominant inheritance was present, but had not been diagnosed because of less severe findings in an affected parent.““ 4) Mildly affected simplex females may be heterozygotes for X-linked retinitis pigmentosa.‘“’ Retinitis pigmentosa is a genetically heterogeneous group of disorders, since mutations at numerous genetic loci must have occurred to account for representation of autosomal dominant and recessive and X-linked modes of inheritance, not to mention the genetic diversity introduced by isolated versus syndromic forms of retinitis pigmentosa. As discussed by Boughman et al,“” genetic studies of retinitis pigmentosa are greatly complicated by both genetic heterogeneity and clinical variability. Furthermore, it is likely that greater heterogeneity within the general category of retinitis pigmentosa will be found at the biochemical or metabolic level, as has been found in other groups of genetic disorders. It is anticipated that numerous different biochemical errors such as primary enzyme deficiencies, structural protein defects or transport problems will account for the final common clinical phenotype of “retinitis pigmentosa.” Such heterogeneity may rise from multiple mutant alleles at a single locus or the presence of multiple loci. For these reasons, investigators have emphasized the need to identify genetically homogeneous groups ot retinitis patients through family studies to obtain more meaningful results from metabolic and linkage studies as well as treatment protocols.‘V”“’ A. AUTOSOMAL

DOMINANT

RETINITIS

PIGMENTOSA

Autosomal dominant retinitis pigmentosa is generallv characterized as a milder disorder with slower pro&ession” and preservation of central vision into the sixth, seventh, or eighth decade.“-’ However, within this genetic type ofretinitis pigmentosa there is a spectrum of phenotypes from early onset severe disease to late onset slowly progressive limited photoreceptor degeneration.” In addition, some pedigrees display reduced penetrance for the gene.“” These observations raise the possibility of either genetic heterogeneity (i.e., the existence of several genetically distinct autosomal dominant disorders with mutations at different gene loci), or variable expression within a single genetic entity (such that the clinical manifestations may range from mild to severe even within the same family). The latter possibility was supported by Boughman”’ who observed a mean difference in age of recognition of first symptoms between siblings with autosomal dominant retinitis pigmentosa of’ 11 .:I years, with a range of more than 40 years.

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Several investigators have suggested classification of autosomal dominant retinitis pigmentosa into clinical phenotypes based primarily on ERG testing and threshold intensity.‘“s2” Fishman et alI” classified patients with severe diffuse pigmentary retinopathy, concentric depression of the visual fields and non-detectable rod and cone responses on ERG as Type 1. This corresponds to Massof-Finkelstein Type lZZ9and pattern D (diffuse ) of Lynes et al”’ in which loss of rod function is diffuse, but loss of cone function may be regional. Fishman Type 2 patients have regional pigmentary changes primarily in the inferior retina, corresponding field defects, abnormal but preserved cone responses on ERG, and elevated rod absolute thresholds. These are similar to Massof-Finkelstein Type 2 patients and pattern R (regional) of Lyness et al in which there is regional loss of both rods and cones. In addition, Fishman described Type 3 patients with sectoral fundus changes, corresponding visual field defects and normal cone implicit times with recordable rod responses on ERG. Type 4 patients had pigmentary changes of the fundus in a demarcated horsehoe or ring configuration, a corresponding partial or complete ring scotoma on visual field testing and well-preserved cone and rod response on ERG. This appears to be an unusually mild form with prolonged preservation ofcentral visual acuity. In the classification of Fishman et al,‘17 there is overlap between Type 2 and Type 3 with the sectoral retinitis pigmentosa phenotype (vide supra), and Massof-Finkelstein Type 2. Types 1 (D) and 2 (R) are roughly equivalent to Types A (no detectable rod ERG) and B (detectable rod ERG) of Arden et al.‘* Type 4 patients with a favorable prognosis have been described by others as having “delimited,“**’ “peripapillary” or “pericentral”255,290 and “arcuate”2s7 retinochoroidal degeneration. Although most of these cases were simplex,255~287~290 there is a report of an affected father and daughter.“’ While there is evidence that Type 1 and Type 2 show intrafamilial the family studies of Lyness et a12” consistency,“’ reveal families in which both patterns occurred, suggesting that further studies are warranted before it can be concluded that these phenotypes reflect specific genetic subtypes of retinitis pigmentosa. Asdiscussed in section 1.B.I above, sector retinitis pigmentosa may represent yet another distinct type of autosomal dominant retinitis pigmentosa. It has also been postulated that autosomal dominant retinitis pigmentosa with reduced penetrance represents a genetic subtype ofautosomal dominant retinitis pigmentosa: 95.43 In such pedigrees there are individuals who are obligate gene carriers by virtue of having an affected parent and an affected child, yet the obligate carrier never develops clinical

PAGON symptoms or manifests changes in rod function even on ERG.S’.‘3 ERG testing of young patients (between the ages of 8 and 15 years) with autosomal dominant retinitis pigmentosa with reduced penetrance revealed normal or slightly reduced cone b-wave amplitudes and substantially delayed cone b-wave implicit times, causing Berson et al to postulate that these findings may be unique to this type of retinitis pigmentosa.35.43 Others”’ have not had the same experience. Boughman and Fishmanj” calculated the penetrance of autosomal dominant retinitis pigmentosa to be as low as 40% even by age 30 years, indicating that a large number of individuals with dominant retinitis pigmentosa may have no family history of retinitis pigmentosa because the other family members who carry the gene are asymptomatic or mildly affected. Initially considered rare, pedigrees with reduced penetrance were observed in 11.5% ( 12 of 104) of families with autosomal dominant retinitis pigmentosa in a recent study.la5 B. AUTOSOMAL PIGMENTOSA

RECESSIVE RETINITIS

Autosomal recessive retinitis pigmentosa is diagnosed in patients who have normal parents and multiple affected siblings or documented parental consanguinity. It tends to be characterized by adolescent onset of deficient dark adaptation with a more rapidly progressive course than autosomal dominant retinitis pigmentosa. Data suggest that more than one form of non-syndromic autosomal recessive retinitis pigmentosa exists5” Patients in which autosomal recessive inheritance has been established are more likely to have a syndromic form of retinitis pigmentosa than those with either the autosomal dominant or X-linked recessive types. Several population studies have revealed that 13-18% of all retinitis pigmentosa patients have a syndrome with associated other that syndromic findings.j9,65 In fact, it appears retinitis pigmentosa accounts for a greater proportion of autosomal recessive cases than isolated retinitis pigmentosa. Therefore, further evaluation for one of the systemic disorders associated with retinitis pigmentosa (Section V) may be warranted in patients with documented or suspected autosoma1 recessive inheritance. C. X-LINKED

RETINITIS

PIGMENTOSA

The X-linked form of retinitis pigmentosa is the least common form, but is recognized to be the most severe, with most affected males having significant visual impairment by the mid-30’s to early 40’s. As with autosomal dominant forms of retinitis pigmentosa, families with an X-linked recessive pattern of

RETINITIS

PIGMENTOSA

Fig. 19. Glistening tapetal-like X-linked retinitis pigmentosa.

1.57

reflex in a carrier

of

inheritance are unlikely to have a syndromic form of retinitis pigmentosa. Bundey and Crews”’ emphasize that 7 of 19 male index cases in their survey did not have a family history to suggest X-linked inheritance, but were diagnosed to have the X-linked form when female relatives were found to have evidence of the carrier state. Since the majority of heterozygous females will have identifiable changes either on fundus examination or ERG testing, evaluation of the mother, maternal grandmother, sisters, or daughters of male simplex cases and sibships of affected males is warranted to determine if an X-linked recessive form is present. Fundus changes in carrier females include the presence of a “tapetal reflex,” a dust-like, golden sheen of the posterior pole (Fig. 19)“” and/or irregular retinal pigment epithelial atrophy with or without associated intraretinal pigment clumping.” Bird described three types of fundus appearance: 1) subtle, but well-defined patches of pre-equatorial pigment epithelial thinning, appearing as slightly gray areas with or without intraretinal pigment clumping; 2) well-defined atrophy of the pigment epithelium and choroid either in the pre-equatorial fundus, or in a segmental or sectoral distribution; or 3) typical findings of retinitis pigmentosa in the midperiphery or posterior pole. Irregular peripheral visual field loss is common and corresponds to the visible fundus abnormalities. The severity and pattern of involvement tends to be symmetric, although asymmetry has been noted in a small proportion of carriers.*H.“4 There is no intrafamilial consistency of heterozygote manifestations. Bird noted a significant proportion of symptomatic heterozygotes among those with fundus changes (3/14), and a tendency of symptoms to increase with age.“” However, even those symptomatic heterozy-

gotes retained lifelong good central vision, The incidence of detectable fundus changes 01 aberrations in tests of visual function in females heterozygous for X-linked retinitis pigmentosa varies in different studies. While Bird’” found abnormalities of the fundus in all 48 heterozygotes examined, other studies have detected fundus changes in a smaller proportion of carriers ( 14 of 23 in a study of Berson et al“” and 40 of 46 in a studv of Fishman et al”‘). Other methods of carrier detection have been proposed. Berson et ap9 determined that on ERG testing in one or both eyes, 22 of 23 (96%) ofobligate heterozygotes had reduction in rod amplitude (19) or delays in ERG cone b-wave implicit time (3) or both. Fishman et alIZ detected an abnormality of cone amplitude, rod amplitude or both in 37 of 43 (86%) carriers; none of the six carriers with normal cone and rod ERG amplitudes had prolonged cone implicit times. In that study, asymmetry in ERG amplitude reduction was noted between the two eyes in seven carriers, illustrating the need to test both eyes when evaluating possible carriers. &-den and coworkers’ ’ tested 22 obligate heterozvgotes and 14 probable heterozygotes bv a similar ERG technique and detected ERG abnormalities in 507~. In that study the severity of ERG changes increased with age, but the ability to detert abnormalities hv ERG was not age-related. Fishman et allZJ determined that 100%’ of carriers could be recognized by the presence of characteristic fundus changes or reductions of ERG amplitude, but concluded that caution is warranted in evaluating potential carriers since it is likely that some carriers would not be identified even utilizing both techniques. Others have suggested that vitreous fluorophotometrp’ iq,l:l;or fundus reflectometry’” are means of distinguishing heterozygotes; these techniques are not widely available for clinical use and it is not clear ifthey offer an advantage over clinical examination and ERG testing. Identification of an X-linked mode of inheritance allows for accurate genetic counseling of affected males and their families and, in some instances, may permit proper diagnosis of heterozygous females with symptoms of“atypica1” or “mild” retinitis pigmentosa. Females heterozygous for X-linked retinitis pigmentosa who have sectoral changes may be phenotypically similar to, and hence confused with, patients with sectoral retinitis pigmentosa or “delimited retinitis pigmentosa,” findings characteristic of autosomal dominant forms of retinitis pigmentosa. D. LINKAGE

STUDIES

Detection of linkage between two genetic allows assignment of a biochemical marker

loci to a

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genetic disorder for which the molecular defect is unknown. Such linkage relationships provide investigational opportunities that are otherwise not possible when the molecular basis of a genetic disorder is not known. For example, prenatal diagnosis, preclinical detection of affected individuals or detection ofcarriers ofan X-linked recessive gene may become possible through such linkage relationships. Also, the presence of linkage to a given marker in some families with retinitis pigmentosa but the absence of linkage to the same marker in other families with retinitis pigmentosa inherited in the same mode establishes genetic heterogeneity for that genetic type of retinitis pigmentosa. Genetic heterogeneity refers to the presence of more than one gene locus that produces the same phenotype. Although the study ofclinical phenotypes within the group of disorders termed retinitis pigmentosa has not been helpful in identifying genetic heterogeneity,56 linkage studies may yield evidence that proves genetic heterogeneity. An additional possible outcome of linkage studies is the chromosomal assignment of the gene in question. Ultimately, linkage studies may permit identification of actual gene loci and characterization of mutant alleles. Recombinant DNA technology provides a new type of genetic marker to be used in traditional linkage studies.g2.g3.536In this approach, restriction endonucleases are used to cleave DNA extracted from cell nuclei into segments known as restriction fragments. These restriction fragments can be separated by size and identified through the use of Southern blot techniques and radiolabeled fragments of DNA (probes). These restriction fragments, which are cut into different lengths as part of normal variation, are termed restriction fragment length of polymorphisms (RFLP). Under ideal circumstances, the exact nature of the DNA mutation causing a disease is known and can be detected directly by DNA analysis after cleavage with a certain restriction endonuclease. However, in most genetic disorders, including all the forms of retinitis pigmentosa, the gene locus and precise genetic abnormality are not known and investigators must rely upon RFLPs to act as DNA markers that “hitchhike” with the disease gene. The presence of the DNA marker gene signifies the presence of the closely linked disease gene. The closer the two genes (i.e., marker and disease gene), the more likely they will be transmitted together; the further apart the two linked genes, the greater the likelihood that they will be separated in the normal process of genetic recombination during gametogenesis. Studies of pedigrees with typical autosomal

PAGON dominant retinitis pigmentosa have revealed no definite linkage to 15 traditional blood group and enzyme markers in one study”” and to 29 traditional biochemical markers in another.“’ Loose linkage of the retinitis pigmentosa locus to the Rh blood group locus on chromosome 1 was suggested in the latter study, but the linkage relationship could not be firmly established. Linkage studies in X-linked retinitis pigmentosa are more promising. Whereas previous studies showed no linkage between the retinitis pigmentosa locus and the blood group Xg” on the terminal short arm of the X chromosome,‘54~‘7g~1Q4 recent studies using a DNA probe designated L1.28 (DXS7) revealed linkage to one gene for X-linked retinitis pigmentosa and localization to the short arm of the X chromosome at Xpl 1 (Fig. 20).46.47.335.537 Others have suggested localization of an X-linked retinitis pigmentosa gene to region Xp2 1 .g5a.‘2g~“16a These disparate findings suggest that there may be more than one retinitis pigmentosa locus on the X chromosome.g2~95a~2~7 Promising as it appears, there may be serious limitations in the use of DNA linkage studies in providing genetic counseling to families.284 These limitations include the following. 1) There is overwhelming likelihood that there are numerous loci (i.e., different genes) for retinitis pigmentosa, such that some loci will display linkage to a given marker and other loci will not. 2) All linkage studies require that DNAfrom both affected and unaffected relatives be available to establish the linkage pattern of that family. 3) The high frequency of DNA polymorphisms (normal variants of the DNA structure) in the general population implies that less than 100% of families will be informative for any given linkage relationship. 4) There is a chance ofinaccurate counseling if the defective gene becomes separated from the linked marker by the process of genetic recombination. Despite these shortcomings, the ability to establish linkage to any of the presumably numerous retinitis pigmentosa loci, such as has been done with the X-linked type, is a positive step both in basic researchg2 and in genetic counseling.261 E. SIMPLEX CASES Simplex cases still comprise half of the ascertained families even after appropriate investigations have excluded a recognized pattern of inheritance and pose significant genetic counseling problems (vide supra). JayIs has made assumptions for genetic counseling cases that depend upon the sex and age of the patient, and clinical severity of the disorder. She calculated that 21% (36/76) of mod-

RETINITIS PIGMENTOSA

22.2

DXS85, 1 3 DXS43

’

*zP

21.2

1

DXS41

]

OTC

3

DXS7

DXS16, DXS9

Xg blood group STS-lchthyosis Ocular albinism CDP-X Retinoschisis

1

Aicardi Syndrome

21.2 21.1 11.~ 1

1

11.2 11.22

-

::s

-

;I; 12

g

_ Pigmentosa ] lncontinentia Pigmenti

1

Ectodermal Dysplasia

12

PGK 3

21.1

r Choroideremia

L

212

]

21.2 q

DXYSl

I

E 22.2

2 ::

DXS3 ]

1

DXS42

25

1

26

] ~xs88

Lowe Syndrome

1

1

HPRT. DXSlO

1

DXS15, DXS52, F8 ]

J

X

Fabry Disease GGPD Deficiency Hunter Syndrome I Adrenoleukodystrophy I Colorblindness - Deu Colorblindness - Pro Blue Cone - Monochromacy

I

21 22

j+

Fig. 20. ldiogram of human X chromosome stained by trypsin G-banding. The retinitis pigmentosa locus at Xpl I is consistant with the data of Wright et a1.31j Others”‘jd.“g have found linkage closer to OTC, ornithine transcarbamylase, at Xp21. Other X-linked disorders of ophthalmic importance are shown along with positions of relevant DNA markers. STS indicates steroid sulfatase deficiency; CDP, chondrodysplasia punctata; C6PD, glucose-6-phosphate dehydrogenase; Deu, deutan; Pro, protan; PGK, phosphoglycerate kinase; HPRT, hypoxanthine phosphoribosyl transferase. (Modified from the third edition ofHoward Hughes Medical Institute Human Gerle Mapping Library1 Chlomosome Plot Book, 1988. Figure courtesy of Richard A. Lewis, M.D.).

erate to severely affected simplex males had Xlinked recessive retinitis pigmentosa, and the reminder had autosomal recessive. Therefore, males with uncertain genetic status who have moderate to severe disease have a negligible chance ofproducing aflected children, but have a 10% chance that each daughter will be heterozygous for the X-linked form. Jayln” postulated that simplex males with mild disease most likely have an autosomal dominant disorder and have an approximately 45% chance of affected offspring. She assumed that the 68% of females who are simplex cases with moderate to severe disease represent autosomal recessive disorders. The 32% that have mild disease may have an autosomal dominant disorder or be heterozygous for the X-linked recessive form. Bundey and Crews”” criticize this approach as attributing too many simplex cases to autosomal recessive inheritance. They calculated empiric risks

for the offspring of simplex probands that may be useful in genetic counseling. If the proband had severe disease and asymptomatic parents, the risk that the offspring would be symptomatic by age 30 years was 218. If the proband had mild disease and asymptomatic parents, the risk of symptoms developing in the offspring by age 30 years was 1137. V.

Retinitis Pigmentosa With Systemic Disorders

Once a patient fulfills the diagnostic criteria for retinitis pigmentosa it is important for patient management and counseling to determine if the retinal dystrophy is an isolated finding or part of a systemic disorder. Systemic disorders in which retinal dystrophy of the retinitis pigmentosa type is a feature are discussed below. Several of these disorders were recently reviewed in detail by Francois.“’ Although the ophthalmologic involvement in some

160

Surv Ophthalmol 33(3) November-December 1988 TABLE 3 Syndromes With Sensorineural Hearing Loss and Retinal Dystrophy

I. Non-progressive 1) Usher syndrome Type I 2) Usher syndrome Type II 3) Congenital adrenoleukodystrophy 4) Infantile phytanic acid storage disease II. Progressive fisher syndrome Type III :i Cockayne syndrome 3) Alstrom syndrome syn4) Mitochondrial myopathy (Kearns-Sayre drome) Refsum syndrome :; Mucopolysaccharidoses I-H, I-H/S, I-S, II, III 7) Edward’s syndrome

of these disorders has traditionally been termed “retinitis pigmentosa,” closer scrutiny reveals that the ocular involvement is more typical of cone-rod dystrophy. Discussion of multisystem disorders with cone-rod dystrophy is included for completeness. Those disorders with sensorineural deafness are listed in Table 3 and those with neurologic involvement in Table 4. A. USHER SYNDROME

The association of retinitis pigmentosa and congenital sensorineural hearing impairment in the absence of other systemic involvement is known as Usher syndrome. It is now recognized that there are at least two and possibly three types of Usher syndrome, all autosomal recessive.‘22~2s4Patients with Type I Usher syndrome have congenital, profound, bilateral sensorineural hearing loss and no intelligible speech. All patients have abnormalities of vestibular nerve function on caloric testing which may cause a mild, nonprogressive ataxia. Symptoms of typical retinitis pigmentosa are usually noted in late childhood to early adolescence and are slowly progressive, resulting in significant visual impairment by the mid-30’s to mid-40’s.267 There is little intrafamilial variability in audiometric (cochlear), vestibular and ocular findings in Type I.‘= Patients with Type II Usher syndrome have a nonprogressive moderate to profound (40 to 60 dB) congenital sensorineural hearing impairment, normal vestibular responses and late-adolescent to young-adult onset of symptoms of retinitis pigmentosa. They generally have intelligible speech. Vision in Type II Usher syndrome is preserved until the 50’s or ~O’S.*~’Severity of ocular and hearing impairment is generally similar within the same family, although the level of hearing impairment, extent of peripheral field loss and degree of fundus pigmen-

PAGON

tary change may show intrafamilial variability.“* The proportion of Usher syndrome patients with the Type I pattern ranges from 90% (Sweden and Finland)‘j6.25” to 60% (Israe1)234 to 34% (USA).‘p? It is not clear if these proportions reflect population differences, bias of ascertainment resulting from selective sampling of more severely affected patients, or both. In all reported series either Type I or Type II Usher syndrome, but not both, occur within a given family, suggesting that they are genetically, as well as clinically, distinct entities. The existence of other types of Usher syndrome is debated. Although Merin et alzs4 proposed that “Type III” include Type I patients with ataxia and be termed “Hallgren syndrome,” they and others’?’ were skeptical that this is a truly distinct entity. Hallgren’56 reported definite, but mild, ataxia in up to 94% of 177 patients with profound hearing loss (Type I). These patients had no other abnormal neurologic findings and the seven who were tested had no vestibular responses on caloric stimulation. Fishman et alIz detected impaired vestibular responses in all Type I patients and concluded that those few Type I patients with clinical ataxia do not constitute a subgroup and that Hallgren was describing typical Type I patients. Merin et alzs4suggested that “Type IV” designate Type I patients with mental retardation since they and others156.527had noted a higher-than-average incidence of mental deficiency in Type I patients. However, they also expressed doubt that this indi-

TABLE 4 Syndromes with Neurologic Involvement and Retinal Qstrophy Mental retardation without neurologic degeneration

Laurence-Moon-Biedl syndrome Infantile phytanic acid storage disease Zellweger syndrome + Juvenile nephronophthisis Mental retardation with neurologic degeneration Cockayne syndrome Neonatal adrenoleukodystrophy Mucopolysaccharidosis: MPS I-H, II, III Normal psychomotor development followed by neurologic degeneration Cockayne syndrome Neuronal ceroid lipofuscinosis Hallervorden-Spatz

Ataxiu, non-progressive

Usher syndrome Type I

Ataxia, progressive

Hallervorden-Spatz (dystonia, spasticity) Spinocerebellar degeneration Mitochondrial myopathy (Kearns-Sayre syndrome) Refsum syndrome Abetalipoproteinemia

RETINITIS

1ti 1

PIGMENTOSA

cated a distinct genetic disorder, but rather represented a response to a double sensory handicap. Nuutila,‘“” who did a comprehensive survey of Usher syndrome in Finland, concluded that true mental deficiency was not increased in Type I patients. Others have suggested that psychiatric disturbance in Type I patients is stress-related and temporally related to the final stages of loss of vision.“‘” More recently “Type III Usher syndrome” has been used to designate the rare association of progressive sensorineural hearing loss with retinitis pigmentosa which appears to comprise less than 1% of all Usher syndrome cases. The age of onset of hearing loss ranges from early childhood,‘,“’ to school age to adulthood.‘““,‘“” This category may prove to be genetically heterogeneous as well. Usher syndrome comprises about 3-6s of the and somewhere between 3%‘” congenitally deaf” and 18%‘” of retinitis pigmentosa patients in the United States, representing the single most common cause of deaf-blindness in this country. The value of early diagnosis to improve the adaptation ofpatients to their disabilities has been emphasized. Early diagnosis of Usher syndrome may offer the possibility of genetic counseling for the parents of an affected child; however, the diagnosis is often not made until late childhood or early adolescence, when many couples would have already completed their families. In the differential diagnosis of Usher syndrome is Alstrom syndrome, Refsum syndrome, and Edwards syndrome. B. LAURENCE-MOON-BIEDL

SYNDROME

The Iaurence-Moon-Biedl syndrome, also called the Bardet-Biedl syndrome, is an autosomal recessive disorder in which some or all of five classic features are observed: retinal dystrophy, mental retardation, obesity, hypogonadism, and postaxial polydactyly.‘“““” Interstitial nephritis of the nephronophthisis type is common, and it has been suggested that nephropathy be considered a majot diagnostic feature as well.‘7’i The retinal dystrophy is characterized as a conered dystrophy’” Often there are minimal fundus changes despite reduced vision and a markedly abnormal ERG.‘“” Of 24 cases reported by Klein and Ammann”“’ 73% were practically blind by age 20 and 86% by age 30 years. Intellectual abilities may range from normal to moderate or severe mental retardation. Klein and Ammann’“s reported a 70 to 85% incidence of mental deficiency in their series. Intellectual deterioration is not observed. Obesity tends to present in childhood and may range from mild to severe. Hypogonadism is more common in

males and appears to be a combination of hypogonadotrophic hypogonadism and end organ failure. Polydactyly, when present, is always postaxial hexadactyly (i.e., a sixth digit arising as part of or adjacent to the fifth finger or fifth toe). Other digital anomalies include syndactyly of toes 2 and 3 or brachydactyly (shortening of digits). Deafness and other malformations such as congenital heart disease are not seen in these patients. ‘The correct nomenclature for this disorder has been debated since some have suggested that there are, in fact, two distinct autosomal recessive disorders: the Bardet-Biedl syndrome:” ’ in which a combination of four of the five classic clinical signs is a necessary and sufficient condition lot diagnosis,L’4.’ and the Iaurence-Moon svndrome. in which mental retardation, retinal degeneration and hypogenitalism occur with spastic paraplegia.“““’ C. COCKAYNE SYNDROME Cockayne syndrome is an autosomal recessive disorder in which healthy infants experience late infantile onset of growth failure and cutaneous photosensitivity to ultraviolet light followed by dementia, cachexia, joint contractures, cerebella] dysfunction, peripheral neuropathy. sensorineural deafness and retinal dystrophy. The fundus appearance is typical for retinitis pigmentosa and most patients have advanced retinal changes by adolescence.x’,x” Cornea1 dvstrophv has been seen in some patients.“’ D. FAMILIAL JUVENILE

NEPHRONOPHTHISIS

Familial juvenile nephronophthisis (Senior syndrome, renal-retinal dysplasia) is an autosomal recessive disorder in which there is a high incidence of retinal dystrophy of the retinitis pigmentosa type ranging from severe (congenital blindness) through typical to mild (sector) retinitis pigmentosa. The renal lesion in familial juvenile nephronophthisis is a chronic, nondestructive, interstitial nephritis that presents with polyuria, polydipsia, and hyposthenuria and often a hypochromic, microcytic anemia. Blood pressure and urine sediment are usually normal. The kidneys are contracted and are characterized histologically by a diffuse interstitial fibrosis and tubular ectasia producing the appearance of cortico-medullary “cysts.““i.“” Hepatic fibrosis with bile duct proliferation associated with minimal hepatic dysfunction is frequently seen in patients with nephronophthisis.““.“” In 1961 the association of this renal lesion with congenital blindness due to retinal dystrophy was recognized by Senior et al.“‘” In subsequent reports it is apparent that the retinal degeneration may be severe, causing congenital blindness.“‘““.“” or may

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be typical retinitis pigmentosa.‘6~26g~2y~At least one patient with sector retinitis pigmentosa and nephronophthisis has been reported.‘40 Others have reported predominant cone involvement.27’ The association of autosomal recessive juvenile nephronophthisis with retinal dystrophy is undisputed, but it not clear if the observed range of severity of retinal involvement reflects variable expressivity within a single autosomal recessive disorder or genetic heterogeneity in which there is but distinct, renal-retinal a group of similar, dysplasias. 13’ Equally perplexing is the finding of mental retardation in a few patients with renalretinal dysplasia.g4,95,?7’ E. ALSTROM SYNDROME In 1959, Alstrom et al” described a rare disorder dystrophy of early now defined’46.53’ by 1) cone-rod onset with nystagmus and progressive impairment of central and peripheral vision such that vision can be severely impaired in late childhood, although some patients have residual vision in the mid-20’s; 2) progressive sensorineural hearing loss beginning about 5-8 years resulting in moderate to severe hearing impairment during adolescence; 3) childhood onset of mild to moderate obesity which may resolve in the 20’s, especially with the onset of renal failure; 4) diabetes mellitus or abnormal glucose tolerance in adolescence with development of insulin-dependent diabetes by the mid-20’s; 5) an interstitial nephropathy that presents with tubular dysfunction and progresses to death from renal failure in the second to fourth decade;R,‘4” 6) hypogonadism with normal secondary sexual development. Males have primary testicular insufficiency;“” females have menstrual irregularity.‘4” Other findings include acanthosis nigricans, elevated serum triglycerides, hyperuricemia, and short staturti3’ Polydactyly has not been reported in Alstrom syndrome. Mental retardation is generally not part of Alstrom syndrome; however, the family reported by Edwards et alto” appeared to have Alstrom syndrome and mental retardation. Whether mental retardation occurs in some patients with Alstrom syndrome or represents the combined effects of sensory deprivation is not clear. F. NEUROLOGIC

DISORDERS

1. Neuronal Ceroid Lipofuscinosis The neuronal ceroid-lipofuscinoses are lysosomal storage diseases involving the accumulation of insoluble autofluorescent lipopigments in a variety of late infantissues.342 Of the five types, the infantile, tile and juvenile forms are associated with a severe early onset retinal dystrophy and neurologic deterioration. Since visual loss precedes neurologic de-

PAGON terioration in the juvenile (Batten-SpielmeyerVogt) type, ophthalmologists need to be alerted to this disorder. The adults5 and atypical’“’ forms are associated with normal vision. The infantile form (Haltia-Santavuori) is an autosomal recessive disorder characterized by normal developmental milestones until about age 8 months. Delays in mental development appear by 12 to 18 months of age; subsequently motor development ceases and hypotonia with trunk and limb ataxia appears. Some patients demonstrate visual impairment by 12 months of age and all have impaired vision by 18 months of age. About 50% have seizures and all have progressive microcephaly and myoclonic jerks by 2 years of age. By 2 to 2M years, all patients have no light perception, absent pupillary responses and uncoordinated eye movements. By age 3 years the children are unresponsive and without voluntary movements. The mean age of death is 6.6 years. Histologically there is severe depletion of neurons in the cerebral and cerebellar cortex with lipofuscin accumulation in the remaining neurons.2g’ Although 3 to 34 cases had normal fundus examinations by ophthalmoscopy in the early stages, all had nondetectable responses on electroretinography and evidence of retinal pigment epithelial atrophy on fluorescein angiography.‘77,“2Z In the late infantile type (Jansky-Bielschowsky), an autosomal recessive disorder, psychomotor development is normal until 2 to 4 years of age. Seizures are usually the first sign, followed in several months by ataxia, arrest in development and behavioral problems. Shortly thereafter loss in motor skills and dementia are apparent and myoclonus becomes a prominent feature. Loss of motor skills is relentlessly progressive to death in decerebrate rigidity 1 to 4 years after onset. Loss of vision occurs concomitantly with the other neurologic degeneration. Ocular findings include optic atrophy and/or intraretinal pigment clumping.2j~“2 The juvenile type (Batten’s disease or Spielmeyer-Vogt), also an autosomal recessive disorder, is typically heralded by rapidly progressing visual loss between the ages of 3M and 7 years before neurologic symptoms or dementia occur. Loss of central vision precedes abnormalities in dark adaptation and visual field constriction suggesting a cone-rod dystrophy. Seizures and dementia often do not follow the onset ofvisual loss for several years. Most patients die of neurologic complications before the age of 20 years. Since ophthalmologists are usually the first physicians to evaluate patients with Batten’s disease, it is important that they recognize the early ophthalmologic manifestations of this disorder, including

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RETINITIS PIGMENTOSA red-green color vision defects and visual loss out of proportion to the macular changes of atrophy and intraretinal pigment clumping. The ERG is not detectable early in the clinical course,‘j’ distinguishing this disorder from juvenile macular degeneration such as Stargardt’s flavimaculatus. Most patients progress to total blindness within a few years after the onset of visual loss. Histologically, there is always a loss of photoreceptors, whether retinal pigmentary changes are limited to the tnacula or are more diffuse.‘“‘-“I’.‘-‘“The biochemical defect(s) causing the neuronal ceroidlipofuscinoses is (are) unknown. A defect in the metabolism of long-chain polyisoprenols of the dolichol type or in the processing of Golgi membranes has been postulated by Ng Ying Kin et al,“’ who have found elevated dolichols in the urine of patients with all three types of neuronal ceroid lipofuscinosis. The diagnosis of neuronal ceroid lipofuscinosis depends on electron microscopic identification of specific inclusions consisting of electron dense, granular aggregates (infantile type), curvilinear bodies (late infantile type) and fingerprint bodies (juvenile type).q” None of these findings are pathognomonic and classification is based primarily on age of onset and clinical findings. Inclusions are identified most easily by electron microscopic examination of lymphocytes that have been concentrated on a Ficbll gradient and prepared as a pellet,“” although biopsy of brain, skin or conjunctiva have been utilized. Prenatal diagnosis ofthe late infantile type has been accomplished by electron microscopy of amniocytes from a pregnancy at risk.“”

2. Hallervorden-Spatz

Syndrome

Dooling et al”’ reviewed the findings in 42 previously reported cases of Hallervorden-Spatz syndrome, an autosomal recessive disorder characterized by: 1) onset at a young age, generally late childhood; 2) extrapyramidal motor dysfunction with dystonic posturing, muscular rigidity, choreoathetoid movements, ataxia, hyperreflexia, and 4) a progressive course spasticity; 3) dementia; leading to death in childhood; 5) specific neuropathologic changes, especially in the globus pallidus and substantia nigra. Almost one-fourth of these 42 cases had retinal degeneration which was described clinically by Newell et arj”” and histologically by Luckenbach et al”” as typical of retinitis pigmentosa. Newell et alZ4’ concluded that patients with the neurologic features of Hallervorden-Spatz syndrome with retinal degeneration had earlier onset and more rapid progression leading to death late in childhood.

3. Spinocerebellar

degenerations

The olivopontocerebellar atrophies (OPCA), previously called Pierre Marie’s hereditary cerebellar ataxia, are a group of diseases characterized by loss of neurons in the cerebellar cortex, basis pontis and inferior olivary nuclei. No specific classification has been widely accepted and terminology is confused regarding subtypes. Retinal dvstrophy has been reported in OPCA III,‘“’ also called autosomal dominant cerebellar ataxia and pigmentary retinal degeneration by Harding.“” This is a distinct autosomal dominant disorder characterized by onset of visual loss, usually in the third or fourth decade, which may either precede or follow the onset of ataxia and tremor. Several families with OPCA III have been reported to have complete external ophthalmoplegia without ptosis.‘““.“” The ophthalmologic involvement has been termed “atypical with more cone involveretinitis pigmentosa” ment.“,“‘,‘“” Decrease in visual acuity and aberrations in color vision often precede changes apparent on ophthalmoscopy and correct diagnosis may be delayed if electroretinographp is not performed. Other reports of ataxia with retinitis pigmentosa include those ofTuck and MacLeod”’ and Cohan et al.“” 4. Hereditary

Motor and Sensory Neuropathy

The association of peripheral motor neuropathy and retinitis pigmentosa in siblings has been termed hereditary motor and sensory neuropathy (HMSN) Type VII by Dyck et al.‘“” 5. Mitochondrial Myopathy (Kearns-Sayre syndrome) Although the retinal lesions of Kearns-Sayre syndrome are not those of retinitis pigmentosa, a discussion of that disorder is included here for completeness. In 1958 Kearns and Sayre reported two patients with pigmentary degeneration of the retina, external ophthalmoplegia and complete heart block.‘“” Numerous case reports of‘ the Kearns-Sayre syndrome ensued, in which the ocular findings can be summarized as: 1) normal dark adaptation and relatively well preserved central visual acuity in the early stages; 2) diffuse severe retinal pigment epithelial atrophy and choroidal atrophy in the peripapillary area or a fine dusting of intraretinal pigment clumping extending from the posterior pole into the far periphery; 3) an enlarged blind spot but generally preserved peripheral isopters on visual field testing; 4) ill-defined and often minor abnormalities on dark adaptation and electroretinography.?+ i&x’,Although the title of Kearns-Sayre’s original report included the term “retinitis pig-

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mentosa,” this appears to be a misnomer for the typical ocular findings of this disorder which is now classified as one of the mitrochondrial myopathies.26.97.209.29R

In a recent series of 61 patients with mitochondrial myopathy, 22 (36%) had pigmentary retinopathy.‘45 The authors describe three different fundus appearances: 18 patients had a “salt and pepper” type of retinal appearance with good vision; two had features of retinitis pigmentosa; and two had generalized loss or atrophy ofthe retinal pigment epithelium and choriocapillaris. Rod responses on ERG testing were detectable in all eleven patients tested and normal in three of the eleven. This study and previous reports do not show convincing similarity between the group of disorders called retinitis pigmentosa and the retinal findings of mitochondrial myopathy. In addition, histologic findings in patients with mitochondrial myopathies’“‘~‘R1~2’2have revealed severe retinal pigment epithelial atrophy and retinal fibrosis without the expected changes of diffuse photoreceptor loss and intraretinal migration of pigment-laden macrophages characteristic of retinitis pigmentosa. G. METABOLIC

DISORDERS

PACON chain fatty acids in plasma or cultured skin fibroblasts and measurement of dihydroxyacetone phosphate (DHAP) acyltransferase activity in cultured skin fibroblasts.Z42 In addition, red blood cell plasmalogen levels are reduced, as is phytanic acid oxidation in cultured skin fibroblasts. (2) Infantile phytanic acid storage disease is an autosomal recessive peroxisomal disorder, in which there are elevated serum levels of phytanic acid and other biochemical evidence of abnormal peroxisoma1 function. Serum phytanic acid levels range from 1.5 to 4.4 mg/dL which is greater than normal but less than the elevation seen in Refsum syndrome. Children with this disorder have hypotonia, moderate to severe developmental delay, profound hearing loss, hepatic dysfunction and retinal dystrophy. Retinal dystrophy develops in the first two years of life. The macula is involved early and the ERG may show equal involvement of rods and cones. The fundus shows retinal pigment epithelial atrophy, especially in the posterior pole near the disc and macula, with coarse intraretinal pigment clumping and retinal vessel attenuation.35s The ophthalmologist may be the first to evaluate an affected individual and in any case will be instrumental in making the diagnosis of this rare peroxisomal disorder.

1. Peroxisomal Disorders

b. Group 2 Disorders

Peroxisomes are organelles present in all animal cells which catalyze the beta oxidation of fatty acids via an enzyme system that is distinct from that of the mitochondria. A number of the peroxisomal disorders, which arejust now being defined and classified biochemically, have a retinal dystrophy and may previously have been considered “complicated Leber’s congenital amaurosis” or “atypical Usher syndrome.” Moser has proposed the following classi1 (abnormal formation or fication: Group maintenance of peroxisomal structure, including Zellweger syndrome and infantile phytanic acid Group 2 (Zellweger variants); storage disease); Group 3 (deficiency of a single peroxisomal enzyme, including Refsum syndrome).242

Little is known about the ophthalmologic festations of these disorders.

a. Group 1 Disorders (1) Zellweger syndrome (cerebra-hepato-renal syndrome) and neonatal adrenoleukodystrophy are autosoma1 recessive disorders manifest in the neonatal period with severe neurologic involvement including profound hypotonia, seizures beginning in the first week of life, enlarged liver, and retinopathy.lgO Recent reports ‘document abnormal electroretinograms’go and photoreceptor degeneration along with the more characteristic loss of ganglion cell and nerve fiber layer in affected infants.87.*8 Diagnosis is made by detection of elevated very long

c. Group

3 Disorders

mani-

(Refsum Syndrome)

Refsum syndrome, an autosomal recessive disorder, was originally called heredopathia atactica polyneuritiformis, and more recently phytanic acid to be one of storage disease.**’ It is now recognized the peroxisomal disorders. First described in two consanguineous Norwegian families by Refsum, it is characterized by retinal dystrophy which presents with defective dark adaptation and visual field constriction usually by age 20 years. These symptoms may antedate the onset of neurologic involvement by several years or as much as one to two decades. Although considered an “atypical” form of retinitis pigmentosa because of minimal early fundus changes,256 patients with advanced disease tend to have more typical fundus changes.15’ Abnormalities of rod and cone function are apparent on ERG testing. Central visual acuity is usually preserved in patients at the time of initial neurologic involvement, but the retinal dystrophy may progress to severe visual impairment within 10 to 15 years of onset of the neurologic symptoms.‘7~‘25~‘9s~‘48 The peripheral neuropathy of Refsum’s disease may present with shooting pains or paresthesias in the limbs and fluctuating, intermittent weakness2”’

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RETINITIS PIGMENTOSA Unexplained and even prolonged remission may occur, but eventually the sensory and motor neuropathy progresses with muscle wasting and weakness of the distal extremities. The presence of palpable peripheral nerves places this disorder in the group of hypertrophic neuropathies.7n The onset of the neuropathy is usually between 20 and 40 years of age, but juvenile onset’2”.2x’ and later onset14” occur. Advanced peripheral neuropathy is often associated with crania1 nerve deficits such as anosomia, miosis, facial weakness, dysphagia and sensorineural deafness and cerebellar involvement including ataxia, dysmetria, intention tremor and nystagmus. Patients with Refsum’s disease have normal mentation, elevated (3SF protein levels in the absence of pleocytosis, generalized ichthyosis that usually appears concomitantly with the neurologic findings. and cardiomyopathy and presumed cardiac arrhythmias causing sudden, unexpected death.‘““,“” Diagnosis is established by detection of phytanir: acid in the plasma. Normal human plasma contains a trace of phytanic acid (less than 0.3 mg/dL) which is usually undetectable in routine analysis, whereas patients with Refsum syndrome have levels ranging from 10 to 30 mg/dL with 5 to 30%’ of the total fatty acids in plasma being phytanic acid.“* The enzyme defect appears to be an error in fatty acid alphaoxidation, probably in the conversion of phytanic acid to alpha-hydroxy-phytanic acid. Some authors recently have suggested screening all patients diagnosed to have retinitis pigmentosa for this disorder since mildly affected patients may have few clinical symptoms.“4 Phytanic acid levels are normal in patients with isolated retinitis pigmentosa. Treatment consists of elimination of dietary sources of phytanate and its precursors in order to reduce plasma and tissue levels ofphytanic acid.2”“,‘1”’ Periodic plasmapheresis may be used as well to mobilize phytanic acid from body fat stores.“’ With such therapy, some neurologic symptoms may improve2H” and retina1 degeneration may be arrested,lix but the magnitude of the benefit to the treated patient is not yet clear. Prenatal diagnosis using amniotic fluid cells should be possible. 2. Mucopolysaccharidoses Of’ the seven established mucopolysaccharidoses,” retinal dystrophy is present only in the types in which heparan sulfate is stored. Those associated with retinal dystrophy are Hurler syndrome (MPS I-H), Sanfilippo syndrome (MPS III), and Scheie syndrome (previously known as MPS V, now classified as MPS l-S).en’ All are autosomal recessive. Interestingly, Hurler syndrome and Scheie syndrome are caused by deficiency of the same enzyme.

alpha-L-iduronidase, but are quite different phenotypically. Hurler syndrome has infantile onset and rapid progression with mental retardation, skeletal dysplasia and death in childhood, whereas patients with Scheie syndrome have normal intelligence, a moderate skeletal dysplasia and survive into adulthood. An intermediate form of MPS I called a Hurler/Scheie compound (MPS I-H/S) is also associated with retinal dystrophy.“’ Patients with Sanfilippo syndrome have severe mental retardation, mild skeletal dysplasia and usually die in adolescence. Two mucopolysaccharidoses have no associated retina1 dystrophy, Morquio syndrome (MPS IV) and Maroteaux-Lamy syndrome (MPS IV).“” Both are autosomal recessive and associated with normal intelligence and moderate to severe skeletal dysplasia. In Hunter syndrome (MPS II), the only X-linked recessive mucopolysaccharidosis, retinal dystrophy appears to be variably associated.““’ The diagnosis ofa mucopolysaccharidosis is made by identification of dermatan sulfate, heparan sulfate, or keratan sulfate in the urine and documentation ofthe specific enzyme defect in skin fibroblast cultures.~‘l None of the five MPS syndromes with retinal dystrophy (MPS I-H, I-S, I-H/S, II, III) initially present with the symptoms of retina1 dystrophy. Thus, the ophthalmologist is unlikely to be involved in the initial diagnosis of such patients. Significant cornea1 clouding is likely to occur in patients with MPS I-H, I-S and VI and if such patients are evaluated for possible cornea1 transplantation, further evaluation for retinal dystrophy is warranted prior to surgery.“’ 3. Abetalipoproteinemia

(Bassen-Kornzweig)

Abetalipoproteinemia, first described by Bassen and Kornzweig,“’ is a rare disorder in which there is defective synthesis of apoprotein B and total absence of beta (low-density) lipoprotein in the plasma of affected individuals. Two genetic disorders produce an identical phenotype: 1) classic abetalipoproteinemia, an autosomal recessive disorder; 2) homozygous autosomal dominant familial hypobetalipoproteinemia.‘““.$,‘” In the absence of apoprotein B there is fat malabsorption and abnormality of red cell shape (acanthocytosis) from birth. Patients usually present in infancy with steatorrhea and failure to thrive. Ataxia, peripheral sensory and motor neuropathy, and retinal dystrophy tend to appear at the end of the first decade, although occasionally the neurologic findings may be the presenting signs. The retinography is characterized by intraretinal pigment accumulation, construction of visual fields and abnormalities of the EOC, ERG and dark adaptation,“;“~‘,“i~ While attempts at treatment

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with vitamin A alone were moderately successful, longterm therapy with large doses of vitamins A and E (100 mg/kg/day) have prevented the development of neuropathy and retinopathy in patients treated prior to age 1 year.5*~243~244 In patients treated with vitamin E after the onset of neuropathy and retinopathy there has been stabilization of the neuropathy, no progression of the pigmentary retinopathy and reversion of the ERG and EOG to norma1.52243 It appears that chronic deficiency of fat soluble vitamins plays a role in the etiology of the neurologic degeneration and retinal dystrophy in this disorder and that combined treatment with vitamins A and E is synergistic.52.24” H. SKELETAL DYSPLASIAS 1. Jeune’s Asphyxiating Thoracic Dystrophy Jeune’s asphyxiating thoracic dystrophy (also known as thoracic-pelvic-phalangeal dystrophy) is an autosomal recessive disorder in which there are characteristic radiographic changes of the pelvis, cone-shaped epiphyses of the phalanges, and variable rib shortening which may cause death from respiratory insufficiency in infancy.25g Patients who do not succumb to respiratory insufficiency in infancy are at high risk for hepatic fibrosis and a fatal progressive interstitial nephritis.‘02 Allen et al7 described the clinical and electrophysiologic findings of typical retinitis pigmentosa in two patients with this disorder, one of whom died at 8% years of age of renal failure and had typical histologic findings of retinitis pigmentosa. These authors emphasize that the prevalance and natural history of retinal involvement in this disorder are not known and warrant further study. 2. Others There have tal dysplasias tosa. 217,266.27U,289 I. OTHER

been case associated

reports of other skelewith retinitis pigmen-

SYSTEMIC DISORDERS

Siblings reported with alopecia, short statue and retinal dystrophy may have a distinct autosomal recessive entity.53 Edwards syndrome is the term used to designate an autosomal recessive disorder of visual impairment in early infancy, progressive sensorineural mental retardation and hypohearing loss, gonadism. 105.351 The early onset ofvisual impairment and almost total blindness in the early 20’s in these patients suggest a cone-rod dystrophy, Seven patients with cone dystrophy and multiple pituitary hormone deficiencies as well as hearing loss were reported by Hansen et a1.1J9Chang et a176reported

PAGON sibling with normal intelligence and hypogonadotrophic hypogonadism and “retinitis pigmentosa.” Although the ophthalmologic findings were not described in any detail, it is possible that this disorder is a distinct autosomal recessive entity. Gordon et a1’+7 described two brothers from a consanguineous mating who had progressive quadriparesis with bulbar involvement, mental retardation, retinitis pigmentosa, and hearing loss.

VI. Pathophysiology A. ANIMAL MODELS FOR RETINITIS PIGMENTOSA Aguirre,2 Matuk,2”’ Lolley,20’ LaVail,2”J and Barnett and Curtis*O have reviewed the pathophysiology of several selected hereditary retinal degenerations in animals and discussed their relationship to human retinitis pigmentosa. The retinal degeneration that occurs in the tanhooded pink-eyed Royal College of Surgeons (RCS) rat is caused by a disturbance in the control of rod outer segment removal. Normally the stacks of membrous discs that comprise the rod outer segments are displaced sclerad by new discs generated at the outer segment base. Groups of discs at the distal end of the outer segment are shed and phagocytized by the retinal pigment epithelium.“3,33g In the RCS rat, failure of the pigment epithelium to phagocytize the shed rod outer segment discs leads to accumulation of rod outer segment debris and photoreceptor degeneration shortly after birth (see LaVail 1981Z03 for review). In mice homozygous for the autosomal recessive retinal degeneration (rd) mutation, there is arrested development of the photoreceptors with degeneration of the rod photoreceptors before cellular maturation is complete. A documented defect in cyclic guanosine monophosphate (cGMP) hydrolysis by cGMP-phosphodiesterase (cGMPPDE) causes markedly elevated intracellular levels of cGMP, known to be toxic to photoreceptors.75~20R In mice homozygous for autosomal recessive retinal degeneration slow (rds), receptor outer segments fail to develop and degenerative changes begin about two weeks of age and result in slow but total loss of visual cells by about one year. The retinas of these animals show low levels ofboth GMP and PDE activity.29” In the dog, generalized “progressive retinal atrophy” (PRA) is a group of autosomal recessive genetic disorders which produce a clinical course similar to human retinitis pigmentosa.*~*” In four of the most studied breeds (miniature poodle, Norwegian elkhound, Irish setter and collie) the age of onset, rate of progression, and type of ERG abnormalities are breed-specific. The PRA present in the Irish

RETINITIS

167

PIGMENTOSA

setter (rod-cone dysplasia I) and collie is biochemically similar to the mouse rd model in that cGMP accumulates in the immature photoreceptors due co reduced activity of a photoreceptor-specific phosphodiesterase. In the Norwegian elkhound (rod dysplasia) and miniature poodle (progressive rodcone degeneration) cGMP phosphodiesterase is normal and the underlying biochemical defect is unknown. In affected poodles there is a reduced rate of photoreceptor renewal, but the significance of this finding in the pathogenesis of PRCD is unknown.” Matings between affected dogs of different breeds produce progeny with normal retinal structure and function, confirming that these disorders in the dog are non-allelic (that is, represent mutations at different genetic loci). It is unknown whether the cGMPPDE defect in these animal retinal degenerations is the pathophysiologic mechanism of human retinitis pigmentosa. Hurwitz et al”’ documented a decrease in this enzyme in the retinas ofa patient with X-linked retinitis pigmentosa. Spiegel et al’“” propose that a defect in transducin, a protein of the rod photoreceptor that activates cGMP phosphodiesterase, ma) play a role in human retinitis pigmentosa. In the cat, a taurine-free casein diet causes pigmentary changes in the central retina, nondetectable ERGS and structural changes indicating photoreceptor degeneration.‘“’ There is evidence that aberrations in taurine metabolism do not pla) a role in human retinitis pigmentosa.J” In addition, patients with retinitis pigmentosa have normal plasma levels of taurine”‘,‘” and earlier studies suggesting a detectable aberration in platelet uptake of taurine in patients with retinitis pigmentosa’ have not been reproducible. I”” B. THEORIES

OF HUMAN

RETINITIS

PIGMENTOSA

Analysis of serum vitamin A”‘” and retinol-binding protein’lq have failed to demonstrate abnormalities in these two aspects of vitamin A metabolism in retinitis pigmentosa. The interphotoreceptor matrix (IPM) is rich in glycosaminoglycans (CAG) and contains the interphotoreceptor retinoid-binding protein (IRBP) which appears to be the principal agent for the transport of retinol between the photoreceptors and the pigment epithelium.” The qualitative pattern of GAG synthesis in cultured retinal pigment epithelium cells from retinitis pigmentosa patients is normal.““” Reported decreases in the IRBP in histologic specimens examined from retinitis pigmentosa patients are difficult to interpret since the decrease may not be causal, but rather secondary to the degeneration of rod photoreceptor cells that are thought to secrete it.““” 2””

The discovery that rod outer segment material was highly antigenic and could produce retinal destruction when injected into experimental animals lead to investigation of the immune system in retinitis pigmentosa patients.“” Several studies have suggested that autoimmunity or altered immune responses may play a primary role in the pathogenesis of photoreceptor degeneration in retinitis pigmentoSa.:‘.W”17”,;,LW however, the possibility that these alterations in immune function represent either a clinically significant secondary response or an epiphenomenon exists.:‘,‘“’ lh9?~INo HLA association has been identified in retinitis pigmentosa patients.“” No abnormalities in serum copper and zinc or erythrocyte superoxide dismutase have been detected.“” C. HISTOPATHOLOGY

OF RETINITIS

PIGMENTOSA

Histopathologic study of an eye enucleated from a healthy 31-year-old male with simplex retinitis pigmentosa and an intraocular tumor provided a clinical-ultrastructural study of well-preserved retina and retinal pigment epithelium.“” The findings corroborated previous suggestions that retinitis pigmentosa results from a primary defect in the rod and cone photoreceptors.“” In the region of the retina corresponding to the patient’s best field of vision, the rod and cone outer segments were shortened and disorganized, but the inner segments were relatively normal (Fig. 21). In the area of visual loss from retinitis pigmentosa there was total loss of outer segments and a decrease in photoreceptor number. Pigmented cells of two types were found invading the retina; typical retinal pigment epithelial cells that were migrating away from the retina1 pigment epithelial layer, and macrophage-like cells that contained melanin. Changes in the retinal pigment epithelium (migration into the retina and reduplication) were interpreted as possibly reactive to photoreceptor damage since the retinal pigment epithelium appeared to be normal morphologically in those areas of early photoreceptor involvement. In all retinal areas the connecting cilia were normal, suggesting that an abnormality of cilia fine structure was not pathogenic, at least in this patient.” Others have also found no evidence for defective cilia in retinitis pigmentosa.“’ Other fine structural analyses include retinas from patients with dominantly inherited retinitis pigmentoSa,lql‘.‘Hti”“..~~’dominantly inherited sectoral retinitis pigmentosa,“’ and X-linked retinitis pigmentosa,‘q’Z Iii as well as a carrier of X-linked retinitis pigmentosa.“”

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VII. Management

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of Retinitis

1988

Pigmentosa

Treatments of retinitis pigmentosa have been explored for decades9* Surgical procedures to increase retinal blood flow have been supplanted by other nostrums, including the consumption of oral preparations (1 I-cis vitamin A, penicillamine, vasodilators), topical therapy (dimethyl sulfoxide (DMSO)), and injections (yeast RNA). Light deprivation has been tried and optical aids (visual field expanders, image intensifiers, high intensity lanterns) have been developed to meet the needs of retinitis pigmentosa patients. Editorials have cautioned that scientifically unfounded treatments are financially and emotionally costly, but may receive popular acclaim from patients and organizations desperately seeking a cure.‘04 Reports of successful treatment have been hampered by poor study design, lack of scientific method, inadequate follow-up, and failure to distinguish genetic subtypes.248 In the past, Berson** has advised that therapeutic trials in retinitis pigmentosa may have the highest yield when the subjects are asymptomatic young people diagnosed early by virtue of a positive family history. However, recent advances in electroretinography permitting objective detection of small changes in retinal function even in individuals with advanced disease suggest that it is now appropriate to consider therapeutic trials in this population as well.” Some have concluded that the rate of visual

Fig.

21. Transmission electron micrograph of retina (approximately 50’ eccentricity) from a 3 1-year-old man with autosomal recessive retinitis pigmentosa. The rod cells (R) show swollen mitochondria and greatly shortened outer segments (OS). The cone cells (C) have lost their outer segments, and their inner segments abut conical shaped protruberances of the retinal pigment epithelium (RPE). CC, connecting cilium; *, zonulae adherentes of the external limiting membrane. X 20,000 magnification. This case was originally reported in Investigative Ophthalmology

and VisualScience24:458-469,1983.

(Photo courtesy Milam, Ph.D.).

of

Ann

Bunt-

PAGON deterioration varies in different individuals and in the same individual at different times, making it difficult to evaluate the possible benefit from a proposed therapy.31” Genetic heterogeneity within the group ofdisorders labeled retinitis pigmentosa makes it highly unlikely that one form of treatment pigmentosa would be effective for all retinitis patients.4g A. VITAMIN A THERAPY Therapy with vitamin A was evaluated in a double-blind study of 27 patients treated twice weekly with 100,000 units of 1 I-cis vitamin A intramuscularly for three years. Thirty control patients were treated in a similar manner with all-trans vitamin A. Measurement of visual acuity, visual fields and dark adaptation revealed improvement in one control patient and one treatment patient and no improvement or regression in comparable numbers of subjects (although statistical analysis was not performed).80 The authors’ conclusion was that 11-cis vitamin A, which is known to protect the viability of the rods and to be essential for the production of rhodopsin, is not of value in the treatment of retinitis pigmentosa. Other studies*“j have lacked proper controls, double-blind methodologies and are presented in a way that may be misleading, i.e., suggesting some effect from therapy when none has been demonstrated.

RETINITIS PIGMENTOSA

I69

B. TOPICAL TREATMENT

is helpful when patients can remain stationary and scan an adequately illuminated area to locate large objects. Cse of a reverse Galilean telescope was found to diminish central visual acuity to an unacceptably low level despite field expansion.“’ More traditional low vision aids such as magnifiers and closed circuit television may provide useful reading vision for patients with reduced central acuity and constricted fields:“:+ Image intensifiers electrically amplify the light available under scoptopic conditions until it surpasses cone threshold and produces an image on a Patients with moderately adphosphor screen. vanced retinitis pigmentosa have improvement in visual thresholds under scoptic conditions with the aid of a monocular Generation II pocketscope.Y” Wide-field, high intensity lanterns produce a bright wide beam of light”’ and improve the nighttime mobility of retinitis pigmentosa patients with constricted held in dim light.“” The de\,ice is inexpensive and allows binocular viewing, but is large, heavy and conspicuous.

Topical treatment with 50% DMSO in aqueous solution to the cornea by eye cup immersion for 30 seconds twice a day was advocated by Hill;“’ however, this study was flawed by inclusion of both retinitis pigmentosa and macular degeneration patients, as well as lack of details regarding diagnostic criteria, length of follow-up, and method of follow-up. Toxicity included burning, dryness and photophobia. Subsequently no improvement was demonstrated in 65 patients and 58 controls in a randomized, masked clinical trial in which followup extended for four to seven years.‘“’ C. LIGHT DEPRIVATION The effects of light deprivation in altering the progression of retinitis pigmentosa was evaluated by Berson’” in two patients with symmetric eye involvement. Both patients occluded one eye with a flushfitting opaque scleral contact lens for 6-8 hours per day for five years. Repeat evaluation of visual acuity, color- vision, dark adaptation thresholds, full-field electroretinograms, visual fields and fundus photography revealed no difference in the rate ofprogression of the retinal degeneration in the occluded and exposed eye. Nevertheless, the recommendation has been made that retinitis pigmentosa patients wear dark glasses during outdoor activities.“O,iy Recently CPF’” 550 lenses (Corning Photochromatic Filter manufactured by Corning Glass Works) which filter out 97 to 99%’ of the spectral and ultraviolet energy below- 550 nm wavelength have been promoted for retinitis pigmentosa patients to increase eye comfort through less glare and less internal scatter, to improve contrast and to reduce adaptation time from light to dark and vice versa. Patient surveys have reflected general, but not unanimous, improvement in these areas. Concerns were decreased ability to distinguish colors and tint density thal was satisfactory for outdoors and bright indoor situations, but too dark for some indoor home settings.Y”,‘“’ D. OPTICAL AIDS Various optical aids have been proposed for patients with peripheral visual loss and preserved central vision, although all have drawbacks. Mirrors and prisms mounted on spectacles for peripheral field expansion are objectionable because of reflection and the inability of the patient to adapt to the necessary changes in eye movement patterns.la40ne type of‘ field expander is a “lookout device” like that used in apartment doors for hallway viewing, but drawbacks include distortion of depth perception and minification of ob_jects in the field which impair patient mobility and reaching.‘“2The field expander

VIII. Summary Retinitis pigmentosa is a term that refers to a heterogeneous group of inherited disorders that affect photoreceptor and retinal pigment epithelial function. This group of disorders collectively is a common cause of visual impairment. Retinitis pigmentosa can occur as an isolated disorder inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner, or it may occur in systemic disorders, which are usually autosomal recessive in inheritance. The retinal dystrophies of such inherited systemic disorders are often more typical of cone-rod dystrophy. Despite the assumption that all the disorders considered to be retinitis pigmentosa are inherited, it is perplexing to note that 50YSofindividuals with retinitis pigmentosa are simplex cases with no family historv of the disorder. Although progress has been made in identifying markers linked to the gene locus for X-linked retinitis pigmentosa, the search for genetic linkage in other forms of retinitis pigmentosa has not been as fruitful. Despite advances in the molecular diagnosis of X-linked retinitis pigmentosa which hold the promise of’ prenatal diagnosis and presymptomatic diagnosis, little is known about the molecular or biochemical basis of the retinal dystrophies with the exception of gyrate atrophy of the retina and choroid and the peroxisomal disorders. No treatment for primary retinitis pigmentosa exists, but patient.s may benefit from treatment of complications such as cataracts and from use ot‘a variety of optical aids. More direct treatment awaits definition of the causative biochemical and molecular defects.

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1988

It is to be anticipated that future molecular genetic research will expand the currently identified genetic linkages to reveal numerous genetic loci and alleles that account for the phenotype of retinitis pigmentosa. Perhaps then early diagnosis, treatment, and genetic counseling will depend on the specific gene defect identified in the laboratory. Acknowledgements

The author is grateful to Robert E. Kalina, M.D., for generous contribution of his advice and photographs, to Maxine Covington for editorial and secretarial assistance, to Kathryn Whitney for secretarial assistance, to Richard Mills, M.D., Ann Bunt-Milam, Ph.D., and Richard G. Weleber, M.D., for critical review of the manuscript, and to Harry Schroeder, M.D., Ph.D. for help with the discussion on molecular genetics.

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RETINITIS

PIGMENTOSA

139. Godel V. laina A. Nemet P. Lazar M: Retinal manifestations in familial juvenile nephronophthisis. Clip Crawl l6:277-281, 1979 140. Godel V, laina A, Nemet P, Lazar M: Sector retinitis pigmentosa in juvenile nephronophthisis. BrJ Ophthulmol 64:124-126, 1980 141. Godel y, Regenbogen I.: I nilateral retinitis pigmentosa and pit ot optic disc. .4rch ~+hthu/mol Y1:1417-1418, 1976 142. Goebel HH. Fix JD, Zeman W: The fine structure of the retina in neuronal reroid-lipofuscinosis. .4m J Ophlhulmol 77:L’.i-39, 195-1 143. (&be] HH. &man L$‘,Damaske E: i\n ultrastructural study 01 the ret ina in the Jansky-Bielschowsky type of neuronal ceroid-lipofuscinosis. .4m J Ophthalmol 83:70-79, 1977 144. Goldman JM, Clemens ME. Gibberd FB, Billimoria JD: SC-reening of patients with retinitis pigmentosa for heredopathia atactica polyneuritiformis (Refsum’s disease). Rr Afrtl] _790:1109-I 1 IO. 1985 l-15. c;oldsteiil EB. Berson EL: Cone dominance of the human early rewptor potential. .\‘~lurr Z-32:1272-1273. 1969 136. (;oldstein JL, Fialkow PJ: The Alstrom syndrome: Report of three cases with further delineation of the clinical, pathoph\ siological. and genetic- aspects of the disorder. ill~di(./t2r ‘i2;5:<-7 I. 1973 147. (;oI-don .ZM. Capute ;iJ, lionigsmark BW: Progressi\ e quadriparesis, mental retardation. retinitis pigmentosa. anti heal-ing 10~5: report of two sibs. John.5 Hopkin.\ Mrd ,I I iA’: I-12-143. lY76 14X. Gordcm N. Hudson REB: Kefsum’s syndrome. Heredopathia Atactica polyneuritiformis: A report of three cases, including a stud\ of the cardiac pathology. Bruzn 824 l-55, 1Yi9 l-11). C;orlm R,J, ‘l‘ilsnvr fJ. Fcinstein S, Duball AJ Ill: Usher-‘s syndrome ‘l)pe 111. .4rc/1 Otolatyngol 105:353-354. 1979 1.50. GOUI-as P: Electroretinograph~: some basic principles. f~iwst Obhthu/mo/ I’I.\ SC? 0:557-569, 1970 151. (;reenwood KS, Nelson JS: Atypical neuronal ceroidlipotilscinosis. ,V~ruro/og? -3Kr510-717, 1978 152. GrizLard \VS. Deutman .4F. Pinckers AJLG: Retinal dystrophies associated with peripheral retinal vasculopathy. Hr ,/ O~~h~hulmol 62; 18X- 194. 1978 I .53. C;rohdahl J: Estimation of prognosis and prevalence of wtinitis pigmentosa and I’sher syndrome in Norway. ~lirr C,r,tr/ 31.255-264. 1987 1%. C.rutinelP, Sanger R. Spivey BE: Linkage studies in X-linked retinitis pigmtntosa. Humnngrn&k 14:155-158, lY72 155. Halpern BL, Sugar A: Retinitis pigmentosa associated with bilateral ectopia lentis. rlntt Ophthalmol 13:823-824, 1981 156. Hallgren B: Retinitis pigmentosa combined with congenital deahless; with vestibule-cerebellar ataxia and mental al)not-malit\ in a proportion of cases. .A clinical and g~lletltv-stat,stical stud! .Wtr I-‘\jthrn!r S-end (sqpt) 238: .i- ItI I , I Y5Y 157. tinnszn E: Famlhal terebro-macular degeneration (tile Stcngel-Batten-Md)ou-Spielmeyer-Vogt-Stock dise.tae): Evaluation of the photoreceptors. .4ctu Ophthulmo/~tg~u ii.S82-396, IYiY 158. Hanben E. Bachen Nl, Flage ‘I-: Refsum’s disease: Eye manifestations in a patient treated with low phytol low phytani, acid diet. .-IIYO Oph~hulmolog~cu 57:899-914, 1979 l.iY. llansen E. l_ar\en IF, Berg I(: A t’amilial syndrome of progresG\e cone dystrophy, degenerative liver disease, rndocrine dystimction and hearing defect. 1. Ophthalmol~~gicnl findings. .4r,/o [email protected]~lmo/og?cl 51: 129-144. 1976 160. I l,cnren RI, Friedman AH, Gartner S, Henkind P: The a\wriation ofretinitis plgmentosa with preretinal macular gliobih. HI-,/ Ophthnlmol hl:5Y7-600, 1Y77 161. Il.udinK hE: (:lassification of the hereditary ataxias and paraplegias. Inlncc~l 1: 1 15 I- 1 155, 1983 162. ti.lr-t mgron DO: The l’i.~uuI I;wld.\. .4 T&&ok and .4tla.\ of (:ltnl~u/ I’wmefry. Saint Louis, (X Mosby. 1976, p 172 163. tieckerrli\el! JR: The lrequency of posterior subcapsular catardct in the hereditdr) retinal degenerations. ,4nr ,/ o~wfn~?so~ 9 i:7:%:I-738. 1’382

163a.Hrckenlively JR: Hrl/rulr\ I’~grrw~~~ov~. t’h~ladc1phia. JB Lippincott. 1YHX 164. Heckenlively JR, BastekJV, Pearlman J’I’, et dl: HLA typing in retinitis pigmentosa. Brj Ophthulmol 6 5: I3 I- 132. 1981 1%. Heckellliveh ,, IR. Solish AM. Chant SM. Meters-Elliott RH. AutoimmunIty in heredit&\ retinal degenerations. II. Clinical studies: antiretinal antibodies and Ruorescein angiogram findings. tlrJ O~hthntmnl hY:7.%-764. IYti.5 I’66. Heckenli\el> JR, ILtleber KC;: S-linked recessive (on< with tapetal-like sheen -Iwh Opt~lt~mlm~~t d\stl-oph) 111-t:1:\+-_ 13”X _> I986 67. Heidemann DC;, Beck RU’: Ketinitls pigmenrusa. A mimic 01’ neurologic disease. .Swz~ Ophthdmo~ 32:4.&i 1, 1987 68. Hellner Kh. Rickers J: Familiar! bilateral segmental rerltlopathin pigmentosa. Ophthulmokgua lhh: 327-341. 1973 6Y. Hendricks RI., Fishman Gi\: 1.) mphoc\ te s&population\ in retinitir pignlentos,l. .-ltf// and S-antigen reactivity Ophtholmol /Oi:6l-65. 198.5 70. Heredia (:I). Huguet J, Co15 N et dl: Immune complexes in retinitis pigmentosa. Hr / Ophthnhol 68.8 I I-X 14. 10X4 I il. IIill RI’: Dimethvl sultijxije in the trratment ot retinal disease. 4rrv .VI’,-lcnd Scr 2-f?:4X.i-lY:\. I!)75 72. Hittner- Ii51, %eller RS: (:eroid-lipofilsciliosis (Batten diaease). lrth Ophthulmol 93:17X-183. 1!)75 7X Holh held J(;, Basinger SF: (:\clic metabolism ot photorweptol- cell<;. /t~w.\t Oph~hulmul I’r\ kr 17:X7-XY. 1978 i-l. tiook~ J,J. Dell-lch-Hook\ B, C,ei\ S. NCMSOIW I): Retinitis plgmrntosa asrociated with ‘I detect In the production oi’ intel.tiron-ganilila. .-Ivf 1 OphMmoi %:755-75X, lYX3 l7.i. Hu 1)s‘: <;eneric aspects of I-etinitis plgmentord in China. .I,ri / .\lrd I;rnr/ 12:.5-56, I!)82 176. Hurler KM. Del-y I’. Sograd) MB. Drummond E;N. The renal lesion of the L.auretl~~-~lootl-Biedl \\ ndrome. / Prdrclt~ 87:X(?-209, 1Y75 177. Iiurv,Itz RL, Bunt-$lilam AH. (:hang Ml.. Bea\o,l.:\: tC;MP })hosphodiestpras~ in rod and cone outet- \cgmvnts of the retina / H/o/ f:hrm ?/50:.56X-573. lYH5 178. Hussels 1: (:ongenital amaur-osib and rlrphrollopllttlisis: d new swdrome. Hlrih Drfec,k: Orig .-lr/ .SPJ I ‘/I( 3j: IYY. 1Yi I 17Y. HLissrls-hlaurrleriee 1, Pierce ER, Bias \VB, Schleutermann I).~: I.inkage studies of typical rrtinitis pigmentosa and common market-s. .4nr / Hum C;PW.~27:505-50X, lY75 IHO. Hy\,arinrtl I.. Rovam0.J. Laurinen P, Peltc)maa A: (‘ontraat se;lsit!vitk tunction m ewluation ot visual inlpairment due tcj retlnitls pigmentosa. .4cla Ophthulmlot iY:76:(-77?, 19X 1 181. lager B\‘. Fred Hl.. Butler RR. C:arnes \VH: Occurrence ot retinal pigmentation. ophthalmoplcgla, ataxla. deafness and heart block. ,4m,/ Afzd 7Y:8XX-XY3, lY60 182. Jampcl KS. Okaraki H. Bernstein H: Ophthalmoplegiaand ‘retinal degeneration associated \zith ~pinowrt+rlla~ ataxia. .-lrch~Ophthn/mol 66;247-2%. I961 183. Jd! 51: On the hereditary 01’ retinltla pigmt,ntosa. 8) / O,bh~trrrlmo/ hh. 40%-116. 1YX” 184. Jose KT, Smith ;?I: Increaslllg periphrl-al held aMarene\s Mith Eresnel prisms. KPL~O$tom I I i:33-57. 1976 185. liaiseI--Kupfer MI. \‘alle D. Bran :\,I: C:linical and blochemical heterogcneit! in gyrate atl-oph\. 1~ / Ophthulmnl ,YY::! 1o-‘~C,‘~ _-... I980 186. Karjalainen S. Terasvirta M. Iiarja J, Kaariamen Ii: An unusllal otologic manifestation of
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pathologic study of retinitis pigmentosa. Ophthal Puedzatr Genet 1:151-168, 1982 Sanyal S, Chader G, Aguirre G: Expression of retinal degeneration slow (rds) gene in the retina of the mouse, in LaVail MM, Hollyfield JG. Anderson RE (eds): Retinal Degeneration: Experimental and Clinical Studies. New York, Alan R. Liss, 1985, pp 239-256 Schachat AP, Maumenee IH: Bardet-Biedl syndrome and related disorders. Arch Ophthalmol 100:285-288, 1982 Schimke R: Hereditary renal-retinal dysplasia. Ann Intern Med 70:735-744, 1969 Schmidt SY, Lolley RN: Cyclic-nucleotide phosphodiesterase. An early defect in inherited retinal degeneration of C3H mice.j Cell Eiol57:117-123, 1973 Schmidt SY, Berson EL, Hayes KC: Retinal degeneration in cats fed casein. I. Taurine deficiency. Invest Ophthalmol Vis Sci 15:47-52, 1976 Seigel RS, Seeger JF, Gabrielsen TO, Allen RJ: Computed tomography in oculocraniosomatic disease (Kearns-Sayre Syndrome). Radiology 1?0:159-164, 1979 Senior B, Friedman A, Brando J: Juvenile familial nephropathy with tapetoretinal degeneration. Am] Ophthalmol52:625-633, 1961 Sieving PA, Fishman GA: Refractive errors of retinitis pigmentosa patients. Br J Ophthalmol 62:163-167, 1978 Silver JH and Lyness AL: Do retinitis pigmentosa patients prefer red photochromic lenses? Ophthal Physiol Opt 5t87-89, 1985 Simell 0, Takki K: Raised plasma-ornithine and gyrate atrophy of the choroid and retina. Lancd i:lO31-1033. 1973 Sipila I, Rapola I, Simell 0, Vannas A: Supplementary cr’eatine as a treaiment for gyrate atrophy of the choroid and retina. N Enpl I Med 304:867-870. 1981 Skalka HW: AsyGmetric retinitis pigmentosa, leutic retinopathy and the question of unilateral retinitis pigmentosa. Acta Ophthalmol 57r35 l-357, 1979 Sorsby A, Franceschetti A, Joseph R, Davey JB: Choroideremia. Clinical and genetic aspects. Br J Ophthalmol 36:547-58 I, 1952 Spallone A, Carlevaro G, Ridling P: Autosomal dominant retinitis pigmentosa and Coats’-like disease. Int Ophthalmol 8:147-151, 1985 Spalton DJ, Bird AC, Cleary PE: Retinitis pigmentosa and retinal oedema. Br J Ophthalmol 62:174-182, 1978 Spence MA, Elston RC, Cederbaum SD: Pedigree analysis to determine the mode of inheritance in a family with retinitis pigmentosa. Clin Genet 5:338-343, 1974 Spencer’ WH: Drusen of the optic disc and aberrant axoolasmic transoort. Ophthalmoloev 85:2 l-38, 1978 Spiigel AM, Gierichik P,‘Levine Mi; Downs RW Jr: Clinical implications of guanine nucleotide-binding proteins as receptor-effector couplers. N Engl J Med 312:26-33, 1985 Stedman’s MedicalDictionary. Baltimore, Williams&Wilkins, 1966, ed 21, pp 714, 1103 Steinberg D: Phytanic acid storage disease: Refsum’s syndrome, in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1983, ed 5, pp 731-747 Sunga RN, Sloan LL: Pigmentary degeneration of the retina: early diagnosis and natural history. Invest Ophthalmol Vis Sci 6:309-325, 1967 Szamier RB: Ultrastructure of the preretinal membrance retinitis pigmentosa. Invest Ophthalmol Vis Sci k!?27-236, 1981 Szamier RB, Berson EL: Retinal ultrastructure in advanced retinitis pigmentosa. Invest Ophthalmol Vis Sci 16:947-962, 1977 Szamier RB, Berson EL: Retinal histopathology ofa carrier of X-chromosome-linked retinitis pigmentosa. Ophthalmol. og?l 92:271-278, 1985 Szamier RB. Berson EL. Klein R. Mevers S: Sex-linked retinitis pigmentosa: ultrastructure ofp’hotoreceptors and pigment epithelium. Invesf Ophthalmol Vir Sri 18:145-160, 1979

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Takahashi M, Jalkh A, Hoskins J, et al: Biomicroscopic evaluation and photography of liquefied vitreous in some vitreoretinal disorders. Arch Obhthalmol 99:1555-1559, 1981 Takki K: Gyrate atrophy of the choroid and retina associated with hyperornithaemia. BrJOphthalmol58:3-23,1974 Takki K: Differential diagnosis between the primary total choroidal vascular atrophies. Br J Ophthalmol 58~24-35, 1974 Takki K, Simell 0: Gyrate atrophy ofthe choroid and retina with hyperornithinemia (HOGA). Birth Defects Orig Art Ser X11(3):373-384, 1976 Tarkkanen A, Haltia M, Merenmies L: Infantile type of neuronal ceroid-lipofuscinosis. J Pediatr Ophthalmol 14:235-241, 1972 Trijbels JMF, Sengers RCA, Bakkeren JAJM, et al: Lornithine-ketoacid-transaminase deficiency in cultured fibroblasts of a patient with hyperornithinaemia and gyrate atrophy of the choroid and retina. Clin Chim Actu 79:371-376, 1977 Tuck RR, McLeod JG: Retinitis pigmentosa, ataxia and peripheral neuropathy. J Neurol Neurosurg Psychiat 46:206-213, 1983 Valle D, Kaiser-Kupfer MI, Del Valle LA: Gyrate atrophy of the choroid and retina: deficiency of ornithine amiotransferase in transformed lymphocytes. Proc NatlAcad Sci 74:5159-5161, 1977 Valle D, Simell 0: The hyperornithinemias, in Standbury JB, Wyngaarden JB, Fredrickson DS, et al (eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1983, ed 5, p 395 Vernon M; Usher’s syndrome: deafness and progressive blindness. J Chron Dis 22:133-151, 1969 Voaden MJ, Hussain AA, Chan PR: Studies on retinitis pigmentosa in man. I. Taurine and blood platelets. BrJ Ophthalmol66:771-775, 1982 reflectometry. Ophthalmologica Weale RA: Fundus 169:30-37, 1974 Weiner LP, Konigsmark BW, Stoll J, Magladery JW: Hereditary olivopontocerebellar atrophy with retinal degeneration. Arch Neural 16:364-376, 1967 Weinstein RL, Kliman B, Scully RE: Familial syndrome of primary testicular insufficiency with normal virilization, blindness, deafness and metabolic abnormalities. N Engl J Med 281:969-977, 1969 Weleber RG, Kennaway NG, Buist NRM: Vitamin B, in management in gyrate atrophy of choroid and retina. Lancet ii.1213, 1978 Weleber RG, Tongue AC, Kennaway NG, et al: Ophthalmic manifestations of infantile phytanic acid storage disease. Arch Ophthalmol 102: 13 17- 132 1, 1984 Weleber RG, Wirtz MK, Kennaway NG: Gyrate atrophy of the choroid and retina: clinical and biochemical heterogeneity and response to vitamin B,. Birth Defects OrigArt Ser 18(6):219-230, 1982 Wright AF, Bhattacharya S, Clayton JF, et al: Linkage relationships between X-linked retinitis pigmentosa and nine short-term markers: exclusion of the disease locus from X~21 and localization to between DXS7 and DXS14. Am 1 Him Genet 41:635-644, 1987 Wrcght AF, Bhattacharya S, Price WH, et al: DNA probes in X-linked retinitis oiementosa. Tram OphthaZmot Sot UK 103:467-474, 1983 ’ ” Wright AF, Dempster M, Jay M, et al: The detection of X-linked RP by DNA hybridization, in LaVail MM, Hollyfield JG, Anderson RE: Retinal Degeneration: Experimental and Clinical Studies. New York, Alan R. Liss, 1985, pp 25-36 Yee RD, Herbert PN, Bergsma DR, Biemer JJ: Atypical retinitis pigmentosa in familial hypobetalipoproteinemia. 4m J Ophthalmol82:64-7 1, 1976 Young RW, Bok D: Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42:392-403, 1969 Yue BYJT, Fishman GA: Synthetic activities of cultured retinal pigment epithelial cells from a patient with retinitis 1

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RETINITIS PIGMENTOSA pigmentosa. .4rch O~hthdmol /03:1563-1566, 1985 341. Zeavin HH, \vald G: Rod and cone vision in retinitis pigmentosa. AmJ Ofihtholmol 42:253-269, 1956 (Batx42. Zeman IV, Dyken P: Neuronal ceroid-lipofuscinosis tcI\‘s disease). Relationship to amaurotic familial idiocy? frrii&c\ 44:.570-583, 1969 :\43. Zollinger- Hr. Mihatsrh MJ. Edefonti A, et al: Nephronophthisis (medullarv cvsric disease of the kidney). H&l I’trrrlrcltr 4ctn 35:.5r&%O, 19x0

Outline I.

II.

Diagnosis and natural history A. Ophthalmologic evaluation of patients SUSpetted to have one of the forms of retinitis pigmentosa 1. History 2. Ocular examination 3. Visual acuity 1. Refractive error 5. Anterior segment and ocular tensions t?. Lens 5. Vitreous 8. Retina 9. Macula 10. Optic nerve 11. Symmetry B. Unusual findings of significance I Sector retinitis pigmentosa 2. Retinitis pigmentosa with exudative vasculopathy 3. Unilateral retinitis pigmentosa Cl. ‘Tests of visual function 1. Electroretinography 2. Dark adaptation and visual sensitivity 3. Visual field 1. Fundus reflectometry 5. Contrast sensitivity 6. Electrooculogram 7. Visually evoked response 8. Fluorescein angiography 9. Vitreous fluorophotometry D. Clinical evaluation of patients 1. Family history 2. Medical historv 3. Laboratory tesiing Differential Diagnosis A. Crnetic disorders that cause retinal degeneration 1. Gyrate atrophy of the choroid and retina 2. Choroideremia 3. Cone-rod dystrophy 4. Cone dystrophy 5. Leber’s congenital amaurosis and early onset retinitis pigmentosa stationary nightblindness 6. Congenital

(Mellai~il) choriDrug exposure - thioridazine oretinopath) C. Infections 1. Syphilitic neuroretinitis 2. Rubella III. Prevalence of retinitis pigmentosa I\‘. Genetics of retinitis pignientosa ;\. ;1utosomal dominant retinit i\ pIgmenlo\a B. Autosomal recessive rrtinitis pignlentc~\Cr (.. S-Linked retinitis pigmentcb\a D. I.inkage studies E. Simplex cases V. Retinitis pigmentosa with svstemic disorder\ A. I..sher syndrome 5. L,aurencc-Moon-Biedl svndl-ome (1. (:ockayne syndrome D. Familial juvenile nephronophthisi> L. .Ustrom svndrome 1.. Neurologic disorders 1. Neuronal ceroid-IipofusciIlosi‘r 2. Hallervorden-Spatz s) ndronre 3. Spinocerebellar degenerations -I. Hereditary motor and sensor-y neuropath! 5. Mitochondrial myoparhl, ( Krarns-SayI-r svndrome) (;. Metabolic Disorders 1. Peroxisomal disorders a. Group 1 disorders ( I) Zellweger syndrome and neonatal adrenoleukodgstrophy (2) Infantile phvtanic acid storage disease b. Group 2 disorders c. Group 3 disorders (KeGurn svndrome) 2. Mucopolysaccharidoses 3. Abetalipoproteinemia (Bassen-Kornzweig) H. Skeletal Dysplasia 1. Jeune’s asphyxiating thoracic dystrophy 2. Others (case reports) Other systemic disorders I. VI. Pathophysiolog!, A. Animal models for retinitis pigmentosa 5. Theories of human retinitis pigmentosa C. Histopathology of retinitis pigmentosa VII. Management of retinitis pigmentosa A. Vitamin A therapy B. Topical treatment C. Light deprivation D. Optical aids VIII. Summary B.

Reprint requests should be addressed to Roberta Pagon. M.D.. Division of Medical Gentics, Children’s Hospital and Medical Center. P.O. Box C-5371. Seattle. WA 9810.5.