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Johannes Birtel, Georg Spital, Marius Book, Sandra Habbig, Sören Bäumner, Vera Riehmer, Bodo B. Beck, David Rosenkranz, Hanno J. Bolz, Mareike Dahmer-Heath, Philipp Herrmann, Jens König, Peter Charbel Issa; Occult retinopathy in patients with severe kidney disease: NPHP1-associated ciliopathy. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3235.
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Nephronophthisis (NPH) is the leading cause of hereditary end-stage kidney disease in children and young adults. Biallelic NPHP1 deletions are the most frequent molecular defect found in NPH patients. Nephrocystin 1, the gene product of NPHP1, is also expressed in photoreceptors where it plays an important role in the intraflagellar transport between the inner and outer segments, but the retinal phenotype has never been investigated in detail. Here, we comprehensively characterized retinal changes in patients with biallelic NPHP1 deletions.
This cross-sectional, multicenter study included 16 patients with a homozygous deletion of the NPHP1 gene. Subjects underwent ophthalmic examination including best-corrected visual acuity (BCVA) testing and retinal imaging.
Median age at examination was 17 years (range, 6-53 years). Fundoscopy and fundus autofluorescence (AF) imaging showed no obvious abnormalities. However, optical coherence tomography (OCT) imaging revealed a distinct retinal phenotype with mild thinning of the outer nuclear layer, reduced reflectivity of the ellipsoid zone, fading or loss of the interdigitation zone, but a preservation of the retinal pigment epithelium. Median visual acuity was 20/20 (range, 20/80-20/20) with a para-central sensitivity loss on visual field testing. Retina-wide function measured with full-field electroretinography revealed either normal responses or a mild cone-dominant dysfunction. Nine patients were asymptomatic, whereas those with visual symptoms mainly reported reduced night vision as initial vision problem. One patient with more severe retinal degeneration carried an additional heterozygous variant in CEP290.
These data suggest that homozygous NPHP1 gene deletions result in a mild retinal ciliopathy that predominantly affects cones, but with relative sparing of the fovea. The distinct retinal phenotype is visible on OCT and usually remains without obvious correlates on clinical examination and AF imaging (“occult retinopathy”). Despite the predominant cone dysfunction on ERG testing, night vision problems may be an early symptom. The identified additional CEP290 variant in the patient with the more severe retinopathy may indicate a potential role for genetic modifiers, although this requires further investigation.
This is a 2021 ARVO Annual Meeting abstract.
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