Adaptive optics imaging of inherited retinal diseases

Georgiou, Michalis; Kalitzeos, Angelos; Patterson, Emily J; Dubra, Alfredo; Carroll, Joseph; Michaelides, Michel

doi:10.1136/bjophthalmol-2017-311328

Cited by 76 publications

(71 citation statements)

References 92 publications

(81 reference statements)

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“…Further work using more detailed imaging techniques, such as adaptive optics scanning light ophthalmoscopy (AOSLO), may better demonstrate the earliest indicators of any structural progression in ACHM. 17 AOSLO allows visualization of individual rod and cone cells in vivo 18 , 19 and has confirmed the presence of cone photoreceptors in all patients with ACHM, albeit reduced in number compared to the unaffected retina, with a wide range of cone densities, and often a disconnect with SD-OCT appearance. 20 With regard to assessing progression of ACHM with AOSLO, Langlo et al 21 demonstrated that foveal cone structure showed little or no change in their cohort of patients with CNGB3 -ACHM over a follow-up period of 6 to 26 months.…”

Section: Discussionmentioning

confidence: 78%

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up

Hirji

Georgiou

Kalitzeos

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeTo longitudinally characterize structural retinal changes in achromatopsia (ACHM) over extended follow-up.MethodsFifty molecularly confirmed ACHM subjects underwent serial spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Foveal structure on SD-OCT was graded and compared for evidence of progression, and foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness were serially measured. FAF patterns were characterized and compared over time.ResultsMean SD-OCT follow-up was 61.6 months (age range at baseline, 6–52 years). Forty-five of the subjects had serial FAF (mean follow-up: 48.5 months). Only 6 (12%) of the subjects demonstrated qualitative change on serial foveal SD-OCT scans. Among the entire cohort, there was no statistically significant change over time in FTRT (P = 0.2459) or hyporeflective zone (HRZ) diameter (P = 0.3737). There was a small—but statistically significant—increase in ONL thickness (P = 0.0084). Three different FAF patterns were observed: centrally increased FAF (13/45), normal FAF (14/45), and well-demarcated reduced FAF (18/45), with the latter group displaying a small gradual increase in the area of reduced FAF of 0.055 mm2 over 43.4 months (P = 0.0011).ConclusionsThis longitudinal study of retinal structure in ACHM represents the largest cohort and longest follow-up period to date. Our findings support the presiding notion that ACHM is essentially a stationary condition regarding retinal structure, and any change over time is likely to be small, slow, and variable across patients. This may potentially afford a wider window for therapeutic intervention.

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Section: Discussionmentioning

confidence: 78%

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up

Hirji

Georgiou

Kalitzeos

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…14 In the same study, Jacobson and associates identified outer nuclear layer thinning over the fovea and decreased intensity of the EZ reflectivity. 14 Further evaluation of retinal structure with adaptive optics ophthalmoscopy may be of value, 37 in order to further elucidate the photoreceptor structure in these patients at a cellular level; however, this will likely be challenging in many patients owing to poor fixation/nystagmus, keratoconus, and early-onset cataract.…”

Section: Discussionmentioning

confidence: 99%

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Bouzia

Georgiou

Hull

et al. 2020

American Journal of Ophthalmology

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The Wellcome Trust (099173/Z/12/Z), Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Retina UK, Fight for Sight UK, and the Foundation Fighting Blindness (USA). Financial Disclosures: Michalis Georgiou and Michel Michaelides consult for MeiraGTx. The other authors have no financial disclosures. All authors attest that they meet the current ICMJE criteria for authorship. Zaina Bouzia and Michalis Georgiou contributed equally and should be considered equivalent authors.

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“…24 Adaptive optic retinal imaging in human CNGB3 and CNGA3 achromatopsia cases has shown a slow decline in foveal cone density and changes in cone reflectivity throughout life. 25 In both the cpfl10 mouse and human cases, cones survive long enough to provide a therapeutic window for treatment.…”

Section: Discussionmentioning

confidence: 99%

A Novel Achromatopsia Mouse Model Resulting From a Naturally Occurring Missense Change in Cngb3

Hassall

Barnard

Orlans

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Hassall MM, Barnard AR, Orlans HO, et al. A novel achromatopsia mouse model resulting from a naturally occurring missense change in Cngb3. Invest Ophthalmol Vis Sci. 2018;59:6102-6110. https://doi.org/ 10.1167/iovs.18-24328 PURPOSE.A local colony of inbred mice (129S6/SvEvTac origin), in isolation for over a decade, were found to have absent light-adapted electroretinogram (ERG) responses. We investigated the inheritance and genetic basis of this phenotype of cone photoreceptor function loss.METHODS. An affected 129S6/SvEvTac colony animal was outcrossed to a C57BL/6J mouse and intercrossed to investigate inheritance in the F2 generation. We performed ERG testing and targeted resequencing on genes of interest (Gnat2, Cnga3, Cngb3, Pde6c, Hcn1, Syne2). The eyes of a subset of animals underwent histologic immunostaining.RESULTS. All 129S6/SvEvTac colony animals tested lacked cone pathway function by ERG testing (n ¼ 12), although rod pathway-based ERG responses remained unaffected. Outcrossintercross breeding showed a recessive inheritance pattern. A novel missense mutation was identified in the Cngb3 gene, which causes an amino acid substitution at a conserved residue (NM_013927)c.692G>A; p.(R231H). The recessive phenotype only affected homozygotes (v 2 ¼ 39, P ¼ 3.2e À10 ). Cones had normal morphology at postnatal day (PND) 70, but cone cell counts declined from PND 30 to PND 335 (P ¼ 0.038), indicating progressive cone photoreceptor death.CONCLUSIONS. We identified the spontaneous occurrence of a 10th model of cone photoreceptor function loss (cpfl10) in an isolated line of inbred mice. Our results indicate that this is caused by a novel missense mutation in the Cngb3 gene, with a fully recessive inheritance pattern. This mouse may provide a more appropriate background against which to assess CNGB3 achromatopsia gene therapy for missense mutations.

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Adaptive optics imaging of inherited retinal diseases

Cited by 76 publications

References 92 publications

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

A Novel Achromatopsia Mouse Model Resulting From a Naturally Occurring Missense Change in Cngb3

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