20 Hereditary Retinal Degenerations
The hereditary retinal degenerations are a group of disorders that both phenotypically and genotypically span a wide spectrum of ophthalmic presentations. In this chapter, the clinical presentation, diagnostic evaluation, treatment, and prognostic factors for each of the more common hereditary retinal degenerations will be discussed. The clinical manifestations of Stargardt’s disease will be touched on; however, more detailed description of disease and management is found in ¦Chapter 19¦, Macular Dystrophies.
20.2 Rod-Cone Retinal Degenerations
20.2.1 Retinitis Pigmentosa
Retinitis pigmentosa (RP) is a group of genetically heterogeneous inherited retinal degenerative disorders characterized by early rod photoreceptor dysfunction followed by progressive rod and cone photoreceptor dysfunction and death. It affects approximately 1 in 4,000 individuals worldwide and may be inherited as an autosomal dominant, autosomal recessive (most common), or X-linked pattern. Nearly 50% of patients with RP have no family history of RP, with the vast majority of these sporadic cases being autosomal recessive. Over 85 genes have been identified in association with RP, which has a wide range of clinical features and severity. Mutations in more than 20 genes are associated with the autosomal dominant form of RP; 20 to 30% are related to mutations in the RHO (rhodopsin) gene. 1 The most common gene involved in the autosomal recessive form is USH2A, which makes up 10 to 15% of autosomal recessive cases. Lastly, the X-linked form is associated with at least six genes, but mutations in RPGR and RP2 genes account for the majority.
The most common form of RP begins with night blindness, or nyctalopia, which may be described as either an inability to visually adapt or a very slow rate of visual adaptation at night. Difficulty seeing in dark conditions can be a problem from early childhood, but in some patients it may not be noticed until the third or fourth decade. RP may also manifest as difficulty with peripheral vision, sometimes expressed by the patient or family members as clumsiness. Visual field loss usually occurs early in the midperiphery (“ring” scotoma) because the midperipheral regions of the retina have the highest concentration of rods. A small central area of vision typically results eventually with disease progression.
Central vision may be good for very long periods of time in many forms of RP. However, there is a general trend of better central vision in the autosomal dominant form and an earlier loss of central vision in the X-linked recessive and autosomal recessive forms. In addition, cystoid macular edema (CME) and posterior subcapsular cataracts are frequent late complications in all genetic varieties of RP, and are important reasons for counseling patients regarding the importance of regular follow-up. 2 Refractive error can contribute to the evaluation of inheritance pattern, as those with X-linked disease are more likely to have 2 diopters or more of myopia, whereas those with a dominant form are usually hyperopic. Color vision can also be helpful with diagnosis, as most patients with isolated RP will have either normal red/green color vision or an acquired deficiency in blue cone function or tritanopia. 1
Although central vision is usually preserved until late in the course of RP, the development of cataracts and CME can lead to earlier and potentially treatable visual acuity loss.
The classic fundus appearance of RP includes what is often referred to as waxy pallor of the disc, caused by either gliosis over the disc or attenuated vessels on the disc; a generalized mottling or “moth-eaten” pattern to the retinal pigment epithelium (RPE); a refractile (tapetum-like) appearance to the retina; narrowed arterioles; and pigment within the retina, as a generalized granularity, more discrete pigment clumps, or pigment deposits appearing as bone spicules (Fig. 20-1). Histologic studies suggest that the source of the pigment is the RPE and that the pigment deposition is secondary to the degenerative process and not a contributing factor to the progress of the disease itself. With the passage of time, there may be progressive atrophy of the RPE and choriocapillaris in both the peripheral retina and the macula, a greater degree of disc pallor, further narrowing of the retinal arterioles until they may resemble white threads, and an increase in pigmentary retinal deposits. Although the majority of patients with typical RP show many or all of the above-mentioned funduscopic changes, there are morphologic variations that may make the diagnosis more difficult on funduscopic evaluation alone. Some patients with RP do not have classic pigmentary clumping in the fundus, and this was formerly referred to as retinitis sine pigmento, which is likely on the spectrum of disease presentation, just observed at an earlier phase of RP. 2
Optic nerve head drusen have been reported to be present more often in patients with RP than in the general population 3 (Fig. 20-2). Histology in one case showed that these were true disc drusen and not astrocytic hamartomas. 4
Visual field testing provides information regarding the rate of visual decline. Commonly used automated visual field strategies are mesopic, confined to the central 55 degrees, and may not provide an accurate assessment of patients’ visual field function.
CME and macular atrophy are easily detectable by optical coherence tomography (OCT) when central vision is affected (Fig. 20-3). The structure–function relationship between the appearances of the photoreceptors in the outer retina on OCT can also help to predict the degree of visual disability including visual field and visual acuity. 5
The full-field electroretinography (ERG) responses are decreased markedly in early stages of RP, making full-field ERG an important diagnostic tool in the diagnosis of RP. Adherence to ERG international standards is essential. Given its dynamic range in RP, the full-field ERG may be near barely detectable levels even at the time of diagnosis in some patients, indicating its limitations in following up patients with RP. While most full-field ERG responses in RP show rod-cone dysfunction where rod responses are affected more severely than cone responses, cone-rod dysfunction also occurs. Of interest, a nondetectable full-field ERG in RP patients does not necessarily imply a total loss of retinal function. For instance, advanced RP patients with a small island of 20/20 vision often have nondetectable full-field ERG responses. 2
Although the above-mentioned findings can be seen in typical cases of RP, there are general differences among the genetic varieties with respect to the rate of progression of the disease and the effect on central vision. 6 The autosomal dominant form of the disease generally progresses more slowly, with a greater retention of visual field as well as preservation of central vision. The X-linked recessive variety seems the most rapidly progressive, with marked peripheral loss by the second decade and severe central vision loss by the mid-30s. 2
In the X-linked recessive form of RP, the female carriers may show a wide spectrum of changes on the basis of lyonization. The majority of patients have no ocular complaints, but there may be a variety of retinal changes. The retina ranges from a normal appearance, to a diffuse pigment mottling, to isolated patches of RPE loss with pigment migration (Fig. 20-4). Some carriers show a tapetum-like change in the parafoveal area. There may be progression of these retinal changes with age, with visual function affected in some patients.
Berson et al 7 have demonstrated the importance of ERG testing to determine the X-linked female carrier. In 95% of such cases, one or both of the following ERG abnormalities will be found: (1) an increased cone b-wave implicit time; (2) a reduction in the amplitude of the dark-adapted response. These studies are important in terms of genetic counseling for those patients who have no retinal abnormalities but may be carriers of the X-linked form of RP.
Genetic testing of known RP genotypes is commercially available from several sources. Because not all RP genotypes are known and because of differences in genotypes tested among laboratories, negative results may be encountered. A comprehensive family tree and determination of hereditary pattern allow a higher yield of positive results.
Management and Course
Patients with RP often feel that complete blindness will be the eventual outcome; however, the majority of such patients never become completely blind, and a small percentage may retain very useful daytime vision all their lives. At present, it is not possible to separate or predict these categories in the early stages of disease. It is equally important to treat patients’ misconceptions and fears as much as to treat the disease itself.
As with all patients with hereditary retinal degenerations, a comprehensive family tree to include affected, unaffected, and potential carrier family members is drawn out to determine potential hereditary pattern. Patient concerns of the disease affecting other family members or future offspring are addressed. Genetic testing is considered depending on the needs of the patient.
Patients with RP are followed up at least every 1 to 2 years if stable. In addition to performing a standard ocular evaluation, a spectral-domain OCT is obtained, particularly in the face of any precipitous loss in vision, as this may signal the possibility of either CME or cataract.
Acetazolamide (Diamox) at a dosage of 125 mg twice a day has been found to be effective in a number of RP patients with CME. A trial for a period of a few months is reasonable to ascertain its effect, which may take up to 6 months to reach maximum effectivity. 8 This dose varies widely from 125 mg every other day to 500 mg daily across many studies. Alternative systemic and local medications for RP-associated CME have been used, such as methazolamide, oral steroid therapy using a derivative of prednisolone, intravitreal corticosteroids, and intravitreal anti–vascular endothelial growth factor agents. 9 In a comprehensive review article by Salvatore et al, the outcomes of each therapy are nicely summarized, ranging from no effect, to morphologic effect only, to a significant improvement in visual acuity. 9 These studies are not limited to patients with RP but include those with juvenile X-linked retinoschisis, Usher’s syndrome, and choroideremia, among others. 10 , 11 Most have a shared multifactorial mechanism including anatomic abnormalities, impairment of the blood–retinal barrier, tangential vitreous traction, and mutations in retinoschin. 9 , 10 , 11 The patient may have rebound edema while on the medication, in which case a trial of holiday from the treatment and reinstatement may be associated with a resumption of its effect. 12
Posterior subcapsular cataracts are seen in approximately 50% of patients with RP and may lead to severe glare and reduction of vision. Although glare itself is often not a sufficient reason to perform cataract surgery, as this can be a common symptom in patients with RP even in the absence of cataracts, the combination of increased glare and decreased vision may make cataract surgery a reasonable option. Such patients should have their potential acuity measured before a decision is made to proceed with cataract surgery because degenerative macular changes may preclude visual improvement. Patients with RP have a higher incidence of zonular instability, so it is important to evaluate for this before surgery and be prepared to insert a capsular tension ring. Finally, there is a higher incidence of posterior capsular opacification in patients with RP, with a rate of 80% reported in one study with approximately 50% of eyes requiring capsulotomy. 13
The most consistent way of following up patients with RP is with visual field evaluation, with the Goldmann’s perimeter being more useful than a more restrictive computerized field. Although certain laboratories have the capability of following up such patients by performing serial ERGs using summated computer 30-Hz cone flicker responses, this is not available in many places.
There has been considerable discussion regarding the pros and cons of therapy with vitamins A, and Berson et al 14 reported that patients with RP who were treated with 15,000 IU of vitamin A per day, in the form retinyl palmitate, had a slower mean rate of decline of retinal function than those who were not treated with vitamin A. The investigators suggested a negative effect of taking 400 IU of vitamin E daily on the course of RP. This report prompted a number of letters, 15 many of which doubted the conclusions of the authors, as much of the conclusion was drawn from ERG testing and not visual fields or visual acuity. At present, it seems that this mode of therapy is still open to question. Another nutritional treatment option for these patients is docosahexaenoic acid (DHA), an omega-3 fatty acid important for photoreceptor function. In a 4-year study of patients with X-linked recessive RP, a dose of 400 mg/day of DHA was not associated with any identifiable safety risks. 16 Another larger study did not show a clear benefit of taking DHA supplements for RP; however, there was a trend toward slower progression of the visual field defect with higher blood concentrations of DHA. 1 A recent Cochrane database review from 2013 concluded that there is no clear evidence for the benefit of treatment with vitamin A and/or DHA for people with RP; however, the Cochrane review did not report on a potential adverse effect of vitamin E. 17 Many patients are well aware of this study, and the conclusions and controversy should be explained to patients before they begin vitamin A treatment or are advised against the use of vitamin E. It is safe to advise a patient that they can avoid supplementation with vitamin E but should not attempt to remove it from their diet. Similarly, patients should be counseled that if they would like to try vitamin A therapy, they should take the retinyl palmitate form and not exceed 15,000 IU daily.
There are ongoing trials to evaluate the efficacy and safety of gene therapy and stem cell therapy in patients with retinal degenerations. The first FDA-humanitarian-approved treatment for RP is the use of an implanted retinal prosthesis known as the Argus II system. This device uses a video camera and implanted retinal chip to relay images via electrical impulses that are transmitted through the optic nerve and down the visual pathway. It is currently approved on a humanitarian basis for those patients with profound RP with bare or no light perception. 18 The device allows patients to perceive high-contrast images and movement, affording them a better circadian rhythm as well as identifying the location or movement of objects or people. Some of the activities tested included locating and touching a square on a white field, recognizing large letters or words, detecting street curbs, and matching black, grey, and white socks. 18
Further treatment includes occupational therapy in low-vision clinics, magnifiers, closed-circuit television, and increased lighting as well as preventative measures such as the use of UVA and UVB blocking sunglasses and the use of CPF 550 lenses to reduce glare and increase adaptation when moving from light to dark.
20.2.2 Syndromic Retinitis Pigmentosa
Although often occurring in isolation, RP can be associated with a systemic disease in approximately 20 to 30% of cases. 1 A list of many of the syndromes associated with RP or a retinal degeneration similar to RP is provided in the following.
Systemic Diseases Associated with Retinitis Pigmentosa
Refsum’s disease (infantile and adult)
Neuronal ceroid lipofuscinosis (Batten’s disease)
Hagberg–Santavuori (early infancy)
Jansky–Bielschowsky (late infancy)
Miscellaneous rare associations
Mucopolysaccharide storage disorders (MPSs)
MPS I-H (Hurler)
MPS I-S (Scheie)
MPS I-H/S (Hurler–Scheie)
MPS II (Hunter)
MPS III (Sanfilippo)
Miscellaneous rare associations
Cerebellar (autosomal dominant)
Mitochondrial myopathy (Kearns–Sayre syndrome)
Miscellaneous rare associations
Renal or hepatic disorders:
Medullary cystic disease (juvenile nephronophthisis; Senior–Løken syndrome; Fanconi’s syndrome)
Zellweger’s syndrome (cerebrohepatorenal syndrome)
In some instances, these are known metabolic disorders, and as such they may provide insight into the basic pathogenetic mechanisms of the retinal disease. Likewise, knowledge of the associations may lead the ophthalmologist to the appropriate systemic disorder. A few of the more common disorders as well as certain disorders for which some therapeutic assistance may be available are discussed. A more complete description of all of them is found in the review article of Bateman et al 19 and in ¦Chapter 22¦.
20.2.3 Usher’s Syndrome
Usher’s syndrome is defined as the association of congenital deafness with RP and is the most common syndromic form of RP. It is the most common form of inherited deaf-blindness with an autosomal recessive pattern and is caused by mutations in at least nine genes.
Although Usher’s syndrome is most commonly divided into three subtypes based primarily on the audiologic clinical presentation, 20 types I and II account for the majority of cases. Type I is defined as profound deafness, usually congenital, vestibular symptoms, and early-onset RP. Patients with type I Usher’s syndrome often do not walk until the age of 18 months. Type II is associated with partial deafness, intact vestibular function, and a milder form of RP. 20 These first two types are heterogeneous and can be caused by eight different genes, while type III has only been associated with one gene to date. 21 Type III is characterized by progressive hearing loss, vestibular function, and retinal changes. 22 Other syndromes of RP with associated deafness are listed as follows.
Syndromes with Deafness and Retinal Degeneration
Enamel dysplasia (Albers-Schönberg)
Refsum (adult and infantile)
Hurler (MPS I)
The exact incidence of Usher’s syndrome is difficult to determine, but surveys among individuals with RP suggest that up to 17% of patients with RP have profound deafness, 21 that 4% of children in schools for the deaf have RP, 23 and that 50% of blind-deaf persons have Usher’s syndrome. 24 The prevalence of Usher’s syndrome in the general population has been estimated to be between 1.8 and 4.4 cases per 100,000. 24 It is important to remember that these patients may also experience vision loss related to CME that is amenable to treatment with topical dorzolamide therapy. 11
20.2.4 Bardet–Biedl Syndrome
In 1920, Bardet 25 described a patient with RP, obesity, and polydactyly; in 1922, Biedl 26 added two other features—namely, mental retardation and hypogenitalism. This now seems a distinct entity from that described by Laurence and Moon 27 60 years earlier—four patients with RP with paraplegia but without polydactyly or obesity, although these were once classified together as Laurence–Moon–Bardet–Biedl syndrome. 28
Most patients do not demonstrate all five features, but for the diagnosis to be established, four of the five, including RP, should be present. It is often inherited in an autosomal recessive form, and more than 10 genes have been identified in causality.
The retinal degeneration usually presents atypically, with central degenerative changes and associated early loss of central vision. Although the peripheral retina may appear relatively normal, often showing the more typical RP changes only later in life, the ERG provides evidence of a generalized retinal degeneration at all stages. Renal abnormalities are also quite common, in one report being present in 90% of autopsy subjects. 29
20.2.5 Neuronal Ceroid Lipofuscinosis (Batten’s Disease)
At present, Batten’s disease includes five distinct entities, all inherited in an autosomal recessive fashion and separated on the basis of clinical and electromicrographic (EM) features. 30 Although the biochemical abnormalities are unknown, there appears to be a difference in the stored lipopigments. 31
The EM features serve to identify the disorders, and gene mapping has placed these disorders at separate chromosomal regions. Of the five types, the two most likely to present to the ophthalmologist are the late infantile form (Jansky–Bielschowsky) and the juvenile form (Spielmeyer–Vogt). All the disorders are characterized by an accumulation of autofluorescent lipopigments in neurons as well as in nonneural tissues. Investigators initially believed that the storage material was the aging pigment lipofuscin and that the yellow pathologic storage lipopigment was ceroid, thus leading to the term neuronal ceroid lipofuscinosis. However, it is now recognized that the storage material is neither ceroid nor lipofuscin but instead contains autofluorescent lipopigments. 32 Histologically, the diagnosis can be made through biopsy of skin or bulbar conjunctiva. 33
There are clinical differences among the varieties. The infantile type typically shows mental and motor abnormalities between the ages of 1 and 1.5 years. Very early visual loss resulting from a generalized retinal degeneration in a child who had been visually normal should suggest this disorder. In addition to a brownish discoloration of the macula and findings of a generalized retinal degeneration, optic atrophy is also observed. The late infantile type has its onset between the ages of 2 and 4 years with seizures and psychomotor deterioration. In this variant, there is both optic atrophy and a generalized degeneration of the retina. 31 The juvenile form is the most common of the variants, and the initial manifestation of the disorder may be decreased vision. The ophthalmoscopic findings of macular degeneration or a bull’s eye maculopathy may lead to the erroneous diagnosis of Stargardt’s disease. However, an ERG will give evidence of widespread photoreceptor degeneration, and eventually an RP-like picture will develop. Somatically, there is progressive mental deterioration and occasionally seizures, with the average age of death being 17 years.
20.2.6 Bassen–Kornzweig Syndrome (Abetalipoproteinemia)
Manifestations of this syndrome, initially described in two siblings in 1950, 34 include malformed erythrocytes (acanthocytosis), neuromuscular disturbances with ataxia, fat intolerance, and RP. The funduscopic changes described in some of the reported cases vary from the typical fundus picture of RP to one with associated scattered deep white deposits. Strabismus and associated nystagmus have also been observed in several patients and may well be related to the central nervous system defect. All psychophysical and electrophysiologic findings are similar to those in any of the generalized retinal degenerations.
Although this autosomal recessive disorder was initially believed to be caused by an absence of beta-lipoprotein, 35 later evidence revealed the metabolic disorder to be more widespread and caused by a mutation in the gene encoding a microsomal triglyceride transfer protein resulting in deficiencies in apolipoprotein (apo) B. 36 , 37 In addition to low serum levels of fats and cholesterol, there is a concomitant lowering of the fat-soluble vitamins, including vitamins A and E, due to malabsorption. Studies have shown that vitamin A and E supplements, in sufficient amounts to raise the serum vitamin A and E to normal levels, lead to normal dark-adapted thresholds and a return of the previously reduced ERG, and help slow the progression of the retinopathy. 38 , 39 It is not known, however, if the retinal degeneration is solely related to vitamin A deficiency or if there is additional causality of the mutation itself. However, the reversal of these changes concurrent with administration of large doses of vitamin A indicates that this may be a treatable form of retinal degeneration. It is important for the ophthalmologist to recognize the possibility of this disease and refer patients for appropriate testing such as a stool sample, blood smear, and lipid workup.
Normalizing serum vitamin A levels with oral vitamin A supplementation can reverse the psychophysical and electrophysiologic abnormalities of Bassen–Kornzweig syndrome. Although the effects on the clinical course of disease are not known, such reversal suggests that this may be a treatable form of RP.
In several respects, the clinical course of the retinal changes in this condition resembles that expected in a retinal deficiency of vitamin A. In both conditions, rod vision deteriorates at an earlier stage than cone vision. This is thought to be a consequence of the fact that the cone visual pigments are synthesized more rapidly than rod pigments, so that when vitamin A is in short supply the needs of the cones are satisfied more effectively than those of the rods.
To establish whether vitamin A deficiency alone is responsible for the retinal degeneration in abetalipoproteinemia, it is important to maintain normal serum vitamin A levels in patients with this disease from the earliest possible age and to use a sensitive index of retinal function, such as the ERG, to check for evidence of retinal dysfunction. Frequent measurements of serum vitamin A levels are also necessary, as these may fluctuate.
20.2.7 Refsum’s Disease
Refsum’s disease (heredopathia atactica polyneuritiformis) is an autosomal recessive disorder predominantly affecting the nervous system. First described in 1945, 40 the characteristic findings in this syndrome are atypical RP with night blindness and constriction of the visual fields, chronic polyneuritis with progressive paresis of the distal parts of the extremities, dry skin, elevated cerebrospinal fluid protein levels, and ataxia with other cerebellar signs. Less frequently observed findings include anosmia, pupillary abnormalities, cataracts, deafness, alteration of the electrocardiogram, and skeletal abnormalities.
Nyctalopia is present in nearly all patients studied and is the most common initial ocular symptom, usually occurring before the third decade of life. The retinal pigmentation is usually a mottled, nondescript type, although a typical bone spicule configuration has sometimes been observed.
In 1963, an abnormal long-chain fatty acid was detected in the serum, urine, kidney, and liver of a patient with Refsum’s disease. 41 This fatty acid—3, 7, 11,15-tetramethylhexadecenoic (phytanic) acid—was subsequently found in other patients with this syndrome. An interesting relationship has been suggested between the abnormal fatty acid and the associated atypical RP. Baum et al 42 hypothesized that palmitic acid, found in its esterified form in high concentration in normal retina, is structurally similar to phytanic acid. There may be an interference, possibly enzymatic, with fatty acid metabolism concomitant with or preceding the incorporation of palmitic acid into the vitamin A ester of the rhodopsin cycle.
Most patients with Refsum’s disease have a deficiency of phytanoyl-coenzyme A (CoA) hydroxylase enzyme activity, leading to an accumulation of phytanic acid, and diagnosis can be made with plasma levels of phytanic acid greater than 200 umol/L. A study of patients with severe neurologic handicaps associated with Refsum’s syndrome showed a remarkable recovery of neurologic function following use of a low-phytanic-acid diet and normalization of their phytanic acid levels. 1 , 43 Although this report makes no mention of patients’ ocular status, more recent studies in such patients have shown some return of retinal function and apparent cessation of the disease process. 44 The infantile form has been described with early RP 45 ; however, dietary restriction in this group of patients was not associated with improvement in retinal function. Despite the lack of long-term follow-up, this disorder may also prove to be one of the treatable forms of RP.
Normalization of the elevated phytanic acid levels in Refsum’s disease by a low-phytanic-acid diet may improve retinal function and halt or slow the progression of disease.