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(Investigative Ophthalmology and Visual Science. 2007;48:1824-1831.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0628
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The Phenotype of Early-Onset Retinal Degeneration in Persons with RDH12 Mutations

Andreas Schuster,1,2 Andreas R. Janecke,2,3 Robert Wilke,1 Eduard Schmid,4 Debra A. Thompson,5,6 Gerd Utermann,3 Bernd Wissinger,7 Eberhart Zrenner,1 and Andreas Gal8

1From the Department of Pathophysiology of Vision and Neuroophthalmology and the 7Molecular Genetics Laboratory, University Eye Hospital, Tübingen, Germany; the 3Departments of Medical Genetics and 4Ophthalmology, Innsbruck Medical University, Innsbruck, Austria; the 5Departments of Ophthalmology and Visual Sciences and 6Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan; and the 8Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Germany.


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To describe the retinal dystrophy phenotype associated with mutations in RDH12, the gene encoding a retinoid dehydrogenase/reductase expressed in the photoreceptor cells.

METHODS. Sixteen persons from 12 families with pathogenic RDH12 mutations on both alleles were studied. Retinal phenotypes were characterized by ophthalmic examination, including psychophysical and standardized electrophysiological methods and multifocal electroretinography (mfERG).

RESULTS. The retinal disease in persons with RDH12 mutations in the homozygous (p.G127X, p.Q189X, p.Y226C, p.A269GfsX1, and p.L274P) or compound heterozygous state (p.R65X/p.A269GfsX1, p.H151D/p.T155I, p.H151D/p.A269GfsX1) was diagnosed initially as Leber congenital amaurosis (LCA) or early-onset retinitis pigmentosa. These individuals appeared to share a common clinical picture, independent of the type of mutation, characterized by poor, yet useful visual function in early life, followed by progressive decline due to both rod and cone degeneration. Marked pigmentary retinopathy, including bone spicules in the peripheral retina, was present in all persons older than age 6, and pronounced maculopathy was evident in persons older than 7 years. A unique view into the progressive nature of the disorder was achieved by evaluation of seven affected persons from three consanguineous families, all carrying the homozygous p.Y226C mutation.

CONCLUSIONS. Ophthalmic findings in persons with RDH12 mutations suggest that RDH12 loss-of-function results in a characteristic form of early and progressive rod–cone degeneration distinct from that caused by mutations in other LCA genes. From our data, it seems likely that various clinical designations appropriately describe the diagnosis in these persons, including early-onset retinitis pigmentosa, LCA type II, and childhood retinal dystrophy.

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous group of rod–cone or cone–rod dystrophies. Although a few families with autosomal dominant inheritance have been reported, typically the condition is transmitted as an autosomal recessive trait. In clinical practice, LCA is diagnosed when there is a marked visual impairment of very early onset (from birth on), whereas the disease is termed juvenile retinitis pigmentosa (RP) if vision loss is evident during the first 2 years of life.1 2 3 Fundus appearance in persons with LCA may initially be normal, although intraretinal pigment deposits, chorioretinal atrophy, white fundus flecks, macular aplasia, and retinal vessel narrowing have been described.4 5 6 The pathologic basis of the visual impairment is a progressive photoreceptor dystrophy as evidenced by severely diminished or absent rod and cone responses on the electroretinogram (ERG).

RDH12 encodes a member of the superfamily of short-chain alcohol dehydrogenases/reductases and is expressed predominantly in photoreceptors.7 Enzymes of this group play a critical role in reactions of the visual cycle responsible for the interconversion of vitamin A (all-trans retinal) to 11-cis retinal, the light-absorbing chromophore of rhodopsin and cone opsins.8 Mutations in genes affecting visual cycle function have been found to be associated with various forms of retinal degeneration, including LCA (for a review, see Ref. 9 ). Recently, RDH12 mutations have been identified in a number of persons diagnosed with severe early-onset rod–cone dystrophy, including LCA, originating from Europe and the United States.10 11 12

In this report, we present detailed analysis of the ocular phenotype of 16 persons from 12 families most likely to be carrying disease-causing mutations of the RDH12 gene, including cross-sectional data from seven persons from three consanguineous families believed to belong to an extended kindred. In this cohort, we found that RDH12 mutations cause an early-onset form of severe retinal dystrophy affecting both rod and cone function and having a phenotype distinct from that resulting from mutations in other known LCA genes.


   Methods
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 Methods
Results
 Discussion
 References
 
Subjects
Informed consent was obtained from all persons involved in the study or from their legal guardians in accordance with the tenets of the Declaration of Helsinki. Linkage mapping and the positional candidate approach first led to detection of patients with the RDH12 mutation p.Y226C in three families.11 Subsequently, we identified RDH12 mutations in 22 DNA samples of 1011 unrelated additional patients with retinitis pigmentosa and LCA.12 We evaluated the comprehensive clinical records from 12 index cases and 4 affected relatives thereof. Detailed clinical findings of these 16 patients (age, 4–69 years) have not been reported previously. Patients initially received a diagnosis of LCA, early-onset RP, or tapetoretinal degeneration, on the basis of typical symptoms and signs of the disease.

Clinical Evaluation
Phenotype analysis consisted of clinical ophthalmic examination, Goldmann perimetry, panel D15 color vision testing, dark-adapted final thresholds, Ganzfeld electroretinography, and multifocal electroretinography (mfERG). Ganzfeld electroretinography was recorded according to ISCEV (International Society for Clinical Electrophysiology of Vision) standards13 (Espion E2 system and ColorDome Ganzfeld stimulator; Diagnosys UK Ltd., Cambridge, UK) using DTL electrodes. White flashes were used at a standard flash intensity of 2.25 cd-s/m2, and for L-cone recordings a single red flash (650 nm) at a flash intensity of 2.25 cd-s/m2 was used. MfERG was performed according to the method described by Sutter and Tran14 (VERIS System; EDI, San Francisco, CA).


   Results
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 Abstract
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Discussion
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Persons Studied
Table 1 summarizes the RDH12 sequence changes identified in the 16 probands included in this study.11 12 A total of 13 persons in nine families had RDH12 mutations in the homozygous state, whereas 3 persons in the three remaining families were compound heterozygous. Within this group, a range of phenotypic presentations was seen, with many cases of severe, early-onset rod–cone degeneration. In most individuals, initial diagnosis was made in early childhood due to visual field constriction, loss of visual acuity, and, often, night blindness.


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  		TABLE 1. RDH12 Mutations and Associated Phenotypic Characteristics

 
Clinical data of persons with RDH12 mutations are presented in this section and summarized in Table 1 .

Night Blindness and Photophobia
All 16 patients reported night blindness with variable age of onset, ranging from early infancy to 20 years. Photophobia was reported only by two of the 16 probands (patients 4 and 5; age >30 years).

Visual Acuity
Visual acuities varied considerably and ranged from 50/100 in the youngest affected individual (proband 13, 4 years old) to light perception in an affected individual 33 years old. Taking into account outside medical records at earlier ages and individual histories of the 16 persons, relatively well-preserved visual acuity in childhood, with values from 10/100 to 50/100, appeared to be a uniform feature in six of seven persons examined at ages 4 to 10 years (patients 1, 7, 8, 14, 15, and 16), and was independent of mutation type. An age-related progressive loss of visual acuity was evident, with values from 10/100 to light perception in persons at ages >20 years.

Refractive Error
Cycloplegic refractions were determined in 14 of the 16 persons and revealed hyperopia >3 D in 3 persons, emmetropia or mild hyperopia ≤3 D in 10 persons, and myopia in 1 person.

Visual Fields
Visual fields were constricted symmetrically. A typical example of constriction of primarily affected, yet preserved, visual fields was seen in patient 7 (Fig. 1C) from family III, belonging to the large Austrian kindred carrying the p.Y226C mutation in the homozygous state. Although less longitudinal data were available for visual fields than for visual acuities, progression in the extent of constriction with time was evident. For example, visual fields were diminished to 20° to 40° in patient 7 at 7 years, to 10° in patient 14 at 9 years, and to 5° in patient 8 at 9 years of age. Most of the patients showed constrictions to <5° at ages >20 years. Visual fields of the seven Austrian patients, all originating from the same region and carrying the same mutation, further support this conclusion (data not shown).


Figure 1
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  		FIGURE 1. Standard ERG waveforms (A), multifocal ERG responses (B), kinetic Goldmann visual fields (C), and color vision testing (D) of the right (RE) and left (LE) eyes of patient 7 (at 7 [B–D] and 8 [A] years of age) compared with an unaffected control subject (norm). (A) The traces of standard ERG waveforms show, from top to bottom, 30-Hz photopic response (trace 1), cone response according to ISCEV standard (trace 2), L-cone response (trace 3), rod-, mixed rod–cone responses, and oscillatory potentials according to ISCEV standard (traces 4, 5, and 6, respectively). Trace 1: cone responses to 30 Hz-flicker stimulation, with amplitudes of 27.96 and 22.37 µV for the right and left eyes, respectively. Trace 2: the cone response with amplitudes of 26.21 and 14.72 µV for the right and left eyes, respectively; trace 3: the L-cone response to a single red flash with an amplitude of 21.86 and 11.61 µV for the right and left eyes, respectively. A rod b-wave could be recorded with an amplitude of 41.41 µV and latency of 99 ms for the right eye, and 15.97 µV/91 ms for the left eye. The scotopic mixed rod/cone responses were detectable with an amplitude of 141.81 µV and latency of 72.5 ms for the right eye and 105.99 µV/48.0 ms for the left eye. Trace 6: oscillatory potentials show no detectable response in either eye. (B) Multifocal ERG responses. Top: Trace array of 61 single traces of the right (left lane) and the left (right lane) eyes. Bottom: average responses from areas of equal eccentricity. The method of scaling and averaging used has been described in Sutter and Tran.14 (C) The visual field test showed relatively well-preserved outer limits for target V/4e and III/4e on the left eye, with increased constriction on the right eye, possibly influenced by compliance problems. The blind spot was not measurable. (D) Saturated panel D15 test shows that color vision was relatively well preserved in both eyes, with only a few changes detected.

 
Color Vision
Panel D15 color vision testing revealed preserved color vision in young probands. In patient 7 (family III; Fig. 1D ) and patient 13 (family IX), aged 7 and 4 years, respectively, a saturated form of the test showed near normal results or only slight changes of the tritan axis. In a 9-year-old individual (patient 14, family X), slight abnormalities of the tritan axis were seen, whereas in a 20-year-old proband (patient 10, family VI) deficiencies in color vision were demonstrated (data not shown). In persons >20 years old, testing was either not possible or revealed massive color vision disturbances.

ERG Recordings
The ERGs available for three young persons (patients 7, 13, and 14) demonstrated a diminished yet still preserved rod and cone function at ages 3, 7, and 9 years, respectively. Both rod and cone ERGs were undetectable in 12 persons between 20 and 69 years of age at the time of recording, including the grandfather of patient 7. No ERG data are available for patient 15, a 70-year-old woman.

Figure 1A shows the ERG responses of patient 7 carrying the p.Y226C mutation in the homozygous state. Rod and rod–cone responses were decreased but recordable. To demonstrate further the preserved central cone function, we recorded multifocal ERGs in patient 7 and found cone responses for all eccentricities, with amplitude reduction and increased implicit times of cone potentials (Fig. 1B) . Foveal responses were relatively more affected than those of more eccentric rings, possibly reflecting the later development of areolar macular atrophy observed in most of the persons with the p.Y226C mutation.

Retinal and Macular Findings
In most cases, some form of pigment retinopathy was present, ranging from mild RPE atrophy and midperipheral hyperpigmentation to marked chorioretinopathy with dense hyperpigmentation. Bone spicules were present in 15 of 16 persons carrying two RDH12 mutations. Even in young persons, mild hyperpigmentation could be observed (Fig. 2A , patient 7, age 7). The presence of more pronounced fundal changes in older persons is exemplified by the fundus of patient 6 (p.Y226C, homozygous) of family III (Fig. 2E) . In patient 8, carrying the p.A269GfsX1 mutation in the homozygous state, a secondary vasoproliferative process with Coats-like appearance was present in the right eye. In patient 9 who was homozygous for p.Q189X, diffuse choroidal atrophy was present (Fig. 2F) .


Figure 2
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  		FIGURE 2. Fundus photographs of persons with RDH12 mutations. For all panels but (C) the left eye is shown. Persons in (A), (C), (D), and (E) are homozygous for the p.Y226C mutation. (A) Patient 7 at age 7 showed partial optic atrophy, moderate vessel attenuation and macular RPE granularity. (B) Patient 8 (homozygous p.A269GfsX1) at age 20 showed macular atrophy and reactive pericentral hyperpigmentation. (C) Patient 3 at 27 years showed marked choroidal and RPE atrophy of the posterior pole, vessel attenuation, and optic atrophy. (D) Patient 1 at age 31 years showed marked choroidal and RPE atrophy of the posterior pole. (E) Patient 6 at age 69 showed macular atrophy and reactive pericentral hyperpigmentation, optic atrophy, and attenuated vessels. Decreased optic quality is due to cataract. (F) Patient 9 (homozygous for p.Q189X) at age 33 showed marked optic and macular atrophy with reactive pericentral hyperpigmentation.

 
Physiological macular reflexes were found in only one affected individual (age 4), whereas various stages of maculopathy were noted in 13 of the 16 patients studied. In two persons, no detailed description of macular changes was available. An areolar form of bilateral macular atrophy was frequently observed (Figs. 2B 2C 2D 2E 2F) and consistently seen in members of the three Austrian families with the p.Y226C mutation. Macular changes were mild only in the youngest affected individual from these families (Fig 2 , age 7). In patient 14 (9 years old), the optic disc appeared normal, whereas various degrees of optic nerve head atrophy were present in all affected persons >10 years old. Retinal vessel attenuation ranged from mild to severe throughout the affected persons in our series.

Cataracts: Anterior Segment
In two young affected persons (patient 13, 4 years old; patient 14, 14 years old), no cataract was observed, whereas in another young person (patient 7, 7 years old) mild subcapsular changes were noted. No clinical details were available for one patient, whereas in the remaining 12 probands with disease-causing RDH12 mutations, all >20 years old, substantial cataract was present, ranging from cortical changes in a few cases to posterior subcapsular cataracts in most of the subjects. In 5 of these 24 eyes, cataract extraction had been performed. Keratoconus was not present in any of the affected persons.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This report presents a comprehensive and comparative clinical description of the ocular phenotype of a cohort of 16 persons with RDH12 mutations. Each patient presented with an early-onset type of severe retinal dystrophy affecting both rod and cone function that was diagnosed as LCA in most cases. They shared a common clinical picture characterized by poor, yet useful visual function in early life, followed by progressive decline of visual function due to both rod and cone degeneration. This conclusion is supported both by the cross-sectional data of our study, and the evaluation of affected persons of different ages from three consanguineous families carrying the p.Y226C mutation, which provides a unique view into the progressive nature of the disorder.

From our data, it seems that various clinical designations might be given as the diagnosis in affected persons with RDH12 mutations, including early-onset RP, LCA type II, or early-childhood retinal degeneration. At young ages (4–6 years), the patients had best visual acuities in the range of 40 to 50/100, and visual fields were relatively well preserved. Residual rod and cone ERG responses were recordable, with preferential preservation of cone function documented by use of multifocal ERG recordings and panel D15 color testing in a 7-year-old child homozygous for the p.Y226C mutation. Most affected persons showed an absence of photophobia, with mild or absent hyperopia or even myopia. Marked pigmentary retinopathy, including bone spicules in the peripheral retina, was present in persons older than age 6, and pronounced maculopathy was evident at ages older than 7 years. Several persons also exhibited posterior subcapsular cataract.

Phenotypic trends have been noted for other LCA genes, including RPE65, GUCY2D, AIPL1, CRB1, CRX, and RPGRIP1.15 16 17 Our current data suggest that the clinical course in persons with RDH12 mutations may be most similar to—yet clearly distinguishable from—that reported for persons with RPE65 mutations.18 19 20 Similarities include preservation of visual acuity, peripheral visual fields, and ERG responses at young ages, as well as absence of photophobia, and mild or absent hyperopia. Differences include the presence of dense bone spicule pigmentation in the peripheral retina, as well as maculopathy at ages older than 7 years that is more pronounced than with RPE65 mutations. In addition, persons with RDH12 mutations retain a relatively higher level of early rod–cone function compared with persons with RPE65 mutations who have nonrecordable ERG responses under scotopic conditions and residual photopic responses only at very young ages.19 Furthermore, posterior subcapsular cataract appears to be more common in persons with RDH12 mutations than in those with RPE65 mutations.

The ocular phenotypes of persons affected by mutations in GUCY2D, AIPL1, CRB1, CRX, and RPGRIP1 appeared to differ from that associated with mutations in RDH12 in our patient cohort. GUCY2D mutations cause a severe, congenital phenotype, with pronounced decrease in visual acuity, constriction of visual fields, and nonrecordable ERGs at the earliest age measured. Early cataract, peripheral hyperpigmentation, and maculopathy are usually not seen.20 21 Persons with AIPL1 mutations also have undetectable ERGs at young ages, presumably due to developmental anomalies and/or photoreceptor cell death. In addition, there is a high frequency of keratoconus.22 23 However, as with RDH12 mutations, macular atrophy and marked bone spicule–like pigmentary changes appear with high frequency. In persons with CRB1 mutations, retinas exhibit small white dots and pigment clumps at early ages, as well as moderate to high hyperopia.24 As with RDH12 mutations, persons with CRB1 mutations exhibit a wide range of visual acuities (from 20/40 to light perception), and decreases to nonrecordable ERG responses. CRX mutations result in a severe, although variable, phenotype. Marked pigmentary retinopathy with bone spicule appearance is observed in less than half of cases; however, marked macular atrophy is present in most cases after age 6.25 26 27 28 In three persons reported to have RPGRIP1 mutations, bone spicule pigmentation and maculopathy were absent, and ERGs were nondetectable in a 15-year-old affected individual.29

The severe and early-onset rod–cone degeneration associated with mutations in RDH12 likely reflects a unique requirement for the encoded enzyme that cannot be met by other RDHs expressed in the photoreceptors, including retSDR1, prRDH, and RDH14.7 30 31 The autosomal recessive mode of inheritance, as well as data from in vitro assays of recombinant enzyme activity suggests that RDH12 mutations result in loss-of-function; however, the associated pathophysiological mechanisms have not yet been elucidated. A better understanding of the role of RDH12 photoreceptor physiology and the existence of animal models of the disease are important tasks for the immediate future.


   Footnotes
 
2 Contributed equally to the work and therefore should be considered equivalent authors. Back

Supported by Grants ZR 1/16-1, ZR 1/17-1 KFO 134 (Erbliche Netzhauterkrankungen) of the Deutsche Forschungsgemeinschaft, Grant P17174 from the Austrian Science Fund, and Grant EVI-GENORET LSHG-CT-2005-512036 from the Commission of the European Union.

Submitted for publication June 9, 2006; revised September 20, 2006; accepted February 12, 2007.

Disclosure: A. Schuster, None; A.R. Janecke, None; R. Wilke, None; E. Schmid, None; D.A. Thompson, None; G. Utermann, None; B. Wissinger, None; E. Zrenner, None; A. Gal, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Robert Wilke, Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital, Schleichstrasse 12-16, D-72076 Tübingen, Germany; robert.wilke{at}med.uni-tuebingen.de.


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