Article

Photoreceptor Structure and Function in Patients with Congenital Achromatopsia

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.66). 07/2011; 52(10):7298-308. DOI: 10.1167/iovs.11-7762
Source: PubMed

ABSTRACT To assess photoreceptor structure and function in patients with congenital achromatopsia.
Twelve patients were enrolled. All patients underwent a complete ocular examination, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinographic (ERG), and color vision testing. Macular microperimetry (MP; in four patients) and adaptive optics (AO) imaging (in nine patients) were also performed. Blood was drawn for screening of disease-causing genetic mutations.
Mean (± SD) age was 30.8 (± 16.6) years. Mean best-corrected visual acuity was 0.85 (± 0.14) logarithm of the minimal angle of resolution (logMAR) units. Seven patients (58.3%) showed either an absent foveal reflex or nonspecific retinal pigment epithelium mottling to mild hypopigmentary changes on fundus examination. Two patients showed an atrophic-appearing macular lesion. On anomaloscopy, only 5 patients matched over the entire range from 0 to 73. SD-OCT examination showed a disruption or loss of the macular inner/outer segments (IS/OS) junction of the photoreceptors in 10 patients (83.3%). Seven of these patients showed an optically empty space at the level of the photoreceptors in the fovea. AO images of the photoreceptor mosaic were highly variable but significantly disrupted from normal. On ERG testing, 10 patients (83.3%) showed evidence of residual cone responses to a single-flash stimulus response. The macular MP testing showed that the overall mean retinal sensitivity was significantly lower than normal (12.0 vs. 16.9 dB, P < 0.0001).
The current approach of using high-resolution techniques to assess photoreceptor structure and function in patients with achromatopsia should be useful in guiding selection of patients for future therapeutic trials as well as monitoring therapeutic response in these trials.

0 Followers
 · 
165 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(2). DOI:10.1101/cshperspect.a017111 · 7.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently we reported on day blindness in sheep caused by a mutation in the CNGA3 gene, thus making affected sheep a naturally occurring large animal model for therapeutic intervention in CNGA3 achromatopsia patients. The purpose of this study was to characterize flicker cone function in normal and day blind sheep, with the aim of generating a normative data base for ongoing gene therapy studies. Electoretinographic (ERG) cone responses were evoked with full-field conditions in 10 normal, 6 heterozygous carriers and 36 day blind sheep. Following light adaptation (10 min, 30 cd/m(2)), responses were recorded at four increasing light intensities (1, 2.5, 5 and 10 cd s/m(2)). At each of these intensities, a single photopic flash response followed by 8 cone flicker responses (10-80 Hz) was recorded. Results were used to generate a normative data base for the three groups. Differences between day blind and normal control animals were tested in two age-matched groups (n = 10 per group). The normal sheep cone ERG wave is bipartite in nature, with critical flicker fusion frequency (CFF) > 80 Hz. In all four flash intensities, the single photopic flash a-wave and b-wave amplitudes were significantly lower (p < 0.005), and implicit times significantly delayed (p < 0.0001), in day blind animals. In all four flash intensities, CFF values were significantly lower (p < 0.0001) in day blind sheep. Cone function is severely depressed in day blind sheep. Our results will provide a normative data base for ongoing gene therapy studies.
    Documenta Ophthalmologica 09/2014; 129(3). DOI:10.1007/s10633-014-9458-6 · 1.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Ciliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple non-human models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia. Methods: A 5 subject open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/day) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for one year. Results: Pupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold or the photopic electroretinogram (ERG). Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors. Conclusions: CNTF did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in responses to CNTF.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14860 · 3.66 Impact Factor

Full-text (2 Sources)

Download
46 Downloads
Available from
May 21, 2014