June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Genotype is a Significant Factor in Determining the Measurability of Atrophic Lesions in ABCA4 disease
Author Affiliations & Notes
  • Winston Lee
    Genetics & Development, Columbia University Irving Medical Center, New York, New York, United States
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • PEI-YIN SU
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • Jana Zernant
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
  • Stephen Tsang
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
    Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
  • Rando Allikmets
    Ophthalmology, Columbia University Irving Medical Center, New York, New York, United States
    Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
  • Footnotes
    Commercial Relationships   Winston Lee Belite Bio, Code C (Consultant/Contractor); PEI-YIN SU None; Jana Zernant None; Stephen Tsang None; Rando Allikmets None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 5409. doi:
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      Winston Lee, PEI-YIN SU, Jana Zernant, Stephen Tsang, Rando Allikmets; Genotype is a Significant Factor in Determining the Measurability of Atrophic Lesions in ABCA4 disease. Invest. Ophthalmol. Vis. Sci. 2023;64(8):5409.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To assess the clinical, genetic and demographic characteristics of patients with “measurable” atrophic lesions in ABCA4 disease.

Methods : The presence and measurability of atrophic lesions on 488-nm autofluorescence (AF) images acquired using the Spectralis HRA+OCT (Heidelberg Engineering), previously defined as definitely decreased autofluorescence (DDAF), was assessed in a genetically confirmed cross-sectional cohort of patients with ABCA4 disease (n=415). Lesion size was determined using the HEYEX software. Circularity index for lesion shape was defined as 4π*area/perimeter2. Mild allele genotypes were defined as those consisting of p.(Gly1961Glu) and/or hypomorphic variants: p.(Asn1868Ile), p.(Thr1526Met), p.(Pro1486Leu), p.(Ile1562Thr), p.(Ala1038Val) and c.[4253+43G>A].

Results : Out of 415 patients, 216 (52%) presented with DDAF in at least one eye. Of these 216, a distinct form of heterogeneous DDAF (h-DDAF) characterized by multiple small coalescing lesions with indistinguishable borders was observed in 28 patients, including all individuals below age 20. After excluding h-DDAF cases, only 79 (out of 188) patients were identified to have measurable lesions on AF – i.e., have lesion with (1) well-defined borders and (2) a perimeter that is entirely visible within a 30° field. The age range of these patients was 24 to 80 years; however the majority of cases fell between 40-60 years (Q1 = 45, Q3 = 58). Mild ABCA4 allele genotypes consisting of p.(Gly1961Glu) and hypomorphic variants comprised 49 out of the 79 (62%) of patients with measurable lesions. Mild allele genotypes were collectively associated with well-defined lesions (P < 0.0001) and the shape of lesions in p.(Gly1961Glu) were the least irregular (circularity index ≈ 0.9) relative to all other ABCA4 genotypes.

Conclusions : Measuring DDAF growth in ABCA4 disease is a suitable endpoint in only a small fraction of patients due to the prevalence of non-quantifiable lesions. Patient cohorts with measurable DDAF lesions will consist largely of middle-aged individuals with mild ABCA4 genotypes. Inclusion of younger patients (below age 20 years) and/or those with severe ABCA4 alleles will require alternative primary endpoints for reliable quantification.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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