Abstract

SO.19.06

Non-syndromic autosomal recessive cone-rod dystrophy and endocochlear hearing impairment in a consanguineous family carrying mutations in the MERTK and DFNB59 gene

Scholl H. P. N.¹, Charbel Issa P.¹, Domeier E.¹, Ebermann I.², Walger M.³, Nürnberg G.^4,5, Lang-Roth R.³, Becker C.^4,5, Nürnberg P.^4,6, Holz F. G.¹, Bolz H. J.^2
1Universitäts-Augenklinik Bonn; ²Institut für Humangenetik, Universitätsklinikum Köln; ³Klinik für Hals-, Nasen-, Ohren-Heilkunde, Kopf- und Hals-Chirurgie, Universitätsklinikum Köln; ⁴Cologne Center for Genomics, Universität Köln; ⁵RZPD Deutsches Ressourcenzentrum für Genomforschung GmbH, Berlin; ⁶Institut für Genetik, Universität Köln

Objective: To describe the phenotype of a consanguineous family from Morocco segregating autosomal recessive cone-rod dystrophy (CORD) and congenital progressive hearing loss (DFBN).
Methods: Best-corrected visual acuity, slit-lamp examination, stereoscopic funduscopy and digital fundus photography, Goldmann kinetic visual fields, electroretinography, fundus autofluorescence imaging (FAF) and high-resolution OCT.
Results: The disease loci were mapped to 2q13-q14.1 for CORD and to chromosome 2q31.1-q32.1 for DFNB, respectively. CORD was shown to be due to homozygosity for a novel splice site mutation in the MERTK gene, c.2189+1G>T, and DFBN due to homozygosity for a 1-bp-insertion in exon 2 (c.113_114insT) of the DFNB59 gene. Two siblings exhibited combined severe CORD and DFBN, three isolated CORD, and one sibling non-syndromic DFBN. The siblings affected by CORD exhibited a very similar phenotype, which was least severe in the youngest sibling (II:1) and most advanced in the oldest (II:6). FAF imaging revealed spotted increased autofluorescence at the posterior pole in II:1 and, to a lesser degree, in II:3. The older siblings showed patches of decreased autofluorescence. High-resolution OCT revealed reduced central retinal thickness, disrupted photoreceptor layer, granular appearance of the RPE layer and a highly reflective irregular nerve fiber layer. Audiological investigation indicated hair cell and vestibular dysfunction.
Conclusions: Although MERTK is generally considered an RP gene, these data confirm recent reports that extended the phenotypic spectrum to severe CORD (McHenry et al. IOVS 2004;45:1456-1463; Tschernutter et al. BJO 2006;90:718-723). The phenotypic severity of the CORD in the siblings correlated well with age. The fundus autofluorescence and high-resolution OCT findings may indicate that in early stages of the disease reduced RPE phagocytosis results in multifocal autofluorescent photoreceptor debris accumulating between the outer retina and the RPE (as in II:1). Ultimately, photoreceptor and RPE cell death would occur as observed in the central macula of the affected individuals.

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