Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G)A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G)A mutation. Results: The c.11864G)A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) (- 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability...
COBISS.SI-ID: 34616281
USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy.
COBISS.SI-ID: 34598361