To define molecular and ophthalmic features of a rare phenotype in autosomal dominant (ad) retinitis pigmentosa (RP)
A 32-year-old woman (proband) with adRP and the low-frequency damped electroretinographic (ERG) wavelet phenotype and her mother were studied with optical coherence tomography (OCT), chromatic perimetry and ERG. A previously reported adRP patient with this ERG phenotype (Lam et al) was also studied with OCT. Genotype in the two families was determined with DNA sequencing.
ERGs from the proband were identical to those reported previously. Chromatic perimetry and ERG stimulus intensity series indicated that there can be severely reduced rod function in addition to substantial cone dysfunction. A heterozygous deletion in peripherin/RDS (Met152del3 atGAA) was present in the patient and the affected mother. There were foveal cystoid changes and pericentral splitting of the inner nuclear layer. ONL thickness and vision tapered with eccentricity, and ‘blind’ regions without discernible ONL showed a thickened, delaminated inner retina. Similar OCT findings were present in the reported adRP patient with this ERG; the patient was heterozygous for a 4-bp deletion (Leu107del4 ctGAGT) in PRPF31.
The low-frequency damped ERG wavelet phenotype is genetically heterogeneous. Inner retinal structural abnormalities are also present in this rare disease expression.
The 32-year-old proband presented with nyctalopia and decreasing visual acuity (VA). Her mother had maculopathy; a maternal aunt had pattern dystrophy (Figure 1a). The maternal grandfather had blindness of unknown cause. Institutional review board approval and informed consent were obtained. Best-corrected VA was 20/25 (+2.25), right, and 20/32 (+1.50), left. There were central cystoid changes, attenuated retinal vessels, bilateral optic nerve drusen, and depigmented-appearing periphery. ERGs showed a barely detectable rod b-wave, reduced a- and b-waves of the mixed cone-rod signal, and reduced and delayed cone responses (Figure 1b). The mixed ERG has low-frequency (20–25 Hz) damped oscillations (50–150 ms after stimulus onset).1 Faster oscillatory potentials were absent. Dark-adapted stimulus-intensity series (Figure 1c) shows an elevated rod b-wave threshold and the characteristic waveform at high intensities. Kinetic fields were full with V-4e, but constricted to I-4e. Chromatic static perimetry demonstrated pericentral-midperipheral rod and cone dysfunction with better-functioning peripheral field (Figure 1d).
Optical coherence tomography (OCT) at age 32 showed central cystoid changes (Figure 2a). Inner nuclear layer (INL) had hyporeflectivity crossed by vertical bands of higher reflectivity (Figure 2a, arrow) in a schisis-like pattern. Outer nuclear layer thinned with eccentricity. At 3 mm temporal, retinal thickness is increased and normal lamination is lost. Serial OCTs demonstrate diminution of central cystoid but persistence of schisis-like changes. A vertical OCT shows central cystoid and, between 1 and 4 mm eccentric, INL splitting. There is no major visual disturbance in the central 2.5 mm: colocalized rod function is within 3 dB of normal lower limit and cone function is normal. Superior to 5 mm, retinal delamination is associated with no measurable vision (Figure 2b).
The proband's 60-year-old mother had long-standing central vision complaints. VA was 20/32 (right) and 20/20 (left). Central retinal pigment epithelium changes were present. Kinetic fields and ERGs were normal. There were no cystoid or schisis-like changes on OCT.
The proband and her mother harboured a heterozygous 3-bp deletion (Met152del3 atGAA) in peripherin/RDS.3 In Family 2, PIII-2 and PIV-1,1 a novel 4-bp deletion (Leu107del4 ctGAGT) of the PRPF31 gene segregated with disease.
The low-frequency damped ERG phenotype is not genotype specific: there is association with mutations in peripherin/RDS or PRPF31. This ERG has now been noted in patients ranging in age from 7 to 32 years.1 Follow-up should clarify whether patients move from stages without wavelets into a wavelet phase and on to more advanced stages with non-detectable ERGs. We also report schisis-like INL changes in this rare disease expression; whether this relates to the pathophysiology is uncertain.
We speculate that the unusual ERG signal may be due to coincidence of two rare phenotypes in the same individual. Rare variations in normal retinal pathways4 could reduce feedback inhibition on inner retinal cells expressing oscillatory behaviour.5 Wavelets may result from unmasking of such oscillations when degeneration causes imbalance in the parallel signal streams traversing the retina.
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This study was supported by grants from Hope for Vision, Foundation Fighting Blindness, Macula Vision Research Foundation, Chatlos Foundation, Research to Prevent Blindness, Ruth and Milton Steinbach Fund, and Alcon Research Institute.
Financial interest: None
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Aleman, T., Lam, B., Cideciyan, A. et al. Genetic heterogeneity in autosomal dominant retinitis pigmentosa with low-frequency damped electroretinographic wavelets. Eye 23, 230–233 (2009). https://doi.org/10.1038/eye.2008.264
- optical coherence tomography
- retinal circuitry
- retinitis pigmentosa
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