Clinical characteristics of early retinal disease due to CDHR1 mutation

Purpose To describe the early clinical and electrophysiological features of cone-rod dystrophy due to a mutation of cadherin-related family member 1 (CDHR1). Methods Three affected siblings from a consanguineous family were ascertained. The clinical data included retinal examination, Goldmann visual fields, fundus autofluorescence imaging, optical coherence tomography (OCT), and pattern and full-field electroretinograms. Exome sequencing was performed in two siblings. Results The three siblings presented at age 24, 18, and 16 years, respectively. Their main symptoms were blurred central vision, dyschromatopsia, and photoaversion. All were myopic with best-corrected visual acuities of 20/60, 20/60, and 20/40, respectively. Fundoscopy revealed a range of macular appearances from mild retinal pigment epithelial changes to symmetric, subfoveal pigmented lesions. Fundus autofluorescence imaging and OCT revealed evidence of mild structural abnormalities in the two older siblings. Electroretinography findings in all three patients indicated severe generalized cone-rod dysfunction. Mutational screening in the three siblings showed them to be homozygous for a previously reported frame-shifting mutation in exon 13 of CDHR1, c.1463delG, p.G488fs. Conclusions The initial clinical signs in this specific retinopathy may be relatively subtle despite a significant functional deficit, with unusual, bilateral, subfoveal pigmented lesions in one 16-year-old patient. Lack of CDHR1 in the human retina causes symptoms related to cone photoreceptor dysfunction in the first instance. A near-normal retinal structure, at least in the first two decades, suggests that CDHR1-related retinopathy may be a good candidate for gene replacement or other novel stabilizing treatments.

[1]  S. Shalev,et al.  A novel splice site mutation of CDHR1 in a consanguineous Israeli Christian Arab family segregating autosomal recessive cone-rod dystrophy , 2012, Molecular vision.

[2]  David M. Wu,et al.  Chapter 44 – Abnormalities of Cone and Rod Function , 2012 .

[3]  Austin Roorda,et al.  Identification of a novel mutation in the CDHR1 gene in a family with recessive retinal degeneration. , 2012, Archives of ophthalmology.

[4]  T. M. Phan,et al.  Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. , 2012, Ophthalmology.

[5]  Donald C. Hood,et al.  ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition) , 2012, Documenta Ophthalmologica.

[6]  B. J. Klevering,et al.  Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. , 2012, American journal of human genetics.

[7]  V. Plagnol,et al.  Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. , 2011, American journal of human genetics.

[8]  J. Veltman,et al.  Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations. , 2010, Investigative ophthalmology & visual science.

[9]  T. Rosenberg,et al.  Mutations in PCDH21 cause autosomal recessive cone-rod dystrophy , 2010, Journal of Medical Genetics.

[10]  Y. Rotenstreich,et al.  Cone-rod dystrophy and a frameshift mutation in the PROM1 gene , 2009, Molecular vision.

[11]  M. Bach,et al.  ISCEV Standard for full-field clinical electroretinography (2008 update) , 2009, Documenta Ophthalmologica.

[12]  S. Bhattacharya,et al.  Biallelic mutation of Protocadherin-21 (PCDH21) causes retinal degeneration in humans , 2008, Molecular vision.

[13]  Mary A. Johnson,et al.  ISCEV standard for clinical pattern electroretinography (PERG): 2012 update , 2007, Documenta Ophthalmologica.

[14]  D. Hunt,et al.  Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. , 2006, Survey of ophthalmology.

[15]  S. Khaliq,et al.  Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy , 2003, Journal of medical genetics.

[16]  J. Nathans,et al.  A Photoreceptor-Specific Cadherin Is Essential for the Structural Integrity of the Outer Segment and for Photoreceptor Survival , 2001, Neuron.

[17]  S. Jacobson,et al.  CORD9 a new locus for arCRD: mapping to 8p11, estimation of frequency, evaluation of a candidate gene. , 2001, Investigative ophthalmology & visual science.

[18]  R. Weleber,et al.  Chapter 40 – Retinitis Pigmentosa and Allied Disorders , 2013 .

[19]  R. Carr,et al.  Chapter 19 – Abnormalities of Cone and Rod Function , 2006 .

[20]  K. Kawasaki,et al.  International society for clinical electrophysiology of vision (ISCEV) , 2006, Graefe's Archive for Clinical and Experimental Ophthalmology.

[21]  Yog Raj Sharma,et al.  Retinitis Pigmentosa and Allied Disorders , 2004 .

[22]  W. Huttner,et al.  A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. , 2000, Human molecular genetics.