Jennifer A. Halder

Frequency of Usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children.

Purpose: Usher syndrome is a major cause of genetic deafness and blindness. The hearing loss is usually congenital and the retinitis pigmentosa is progressive and first noticed in early childhood to the middle teenage years. Its frequency may be underestimated. Newly developed molecular technologies can detect the underlying gene mutation of this disorder early in life providing estimation of its prevalence in at risk pediatric populations and laying a foundation for its incorporation as an adjunct to newborn hearing screening programs.Methods: A total of 133 children from two deaf and hard of hearing pediatric populations were genotyped first for GJB2/6 and, if negative, then for Usher syndrome. Children were scored as positive if the test revealed ≥1 pathogenic mutations in any Usher gene.Results: Fifteen children carried pathogenic mutations in one of the Usher genes; the number of deaf and hard of hearing children carrying Usher syndrome mutations was 15/133 (11.3%). The population prevalence was estimated to be 1/6000.Conclusion: Usher syndrome is more prevalent than has been reported before the genome project era. Early diagnosis of Usher syndrome has important positive implications for childhood safety, educational planning, genetic counseling, and treatment. The results demonstrate that DNA testing for Usher syndrome is feasible and may be a useful addition to newborn hearing screening programs.

Autosomal Recessive Retinitis Pigmentosa Caused by Mutations in the MAK Gene

PURPOSE To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. METHODS Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). RESULTS All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. CONCLUSIONS The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

Monomeric C-reactive protein and inflammation in age-related macular degeneration.

Age‐related macular degeneration (AMD) is a devastating disease characterized by central vision loss in elderly individuals. Previous studies have suggested a link between elevated levels of total C‐reactive protein (CRP) in the choroid, CFH genotype, and AMD status; however, the structural form of CRP present in the choroid, its relationship to CFH genotype, and its functional consequences have not been assessed. In this report, we studied genotyped human donor eyes (n = 60) and found that eyes homozygous for the high‐risk CFH (Y402H) allele had elevated monomeric CRP (mCRP) within the choriocapillaris and Bruchs membrane, compared to those with the low‐risk genotype. Treatment of choroidal endothelial cells in vitro with mCRP increased migration rate and monolayer permeability compared to treatment with pentameric CRP (pCRP) or medium alone. Organ cultures treated with mCRP exhibited dramatically altered expression of inflammatory genes as assessed by RNA sequencing, including ICAM‐1 and CA4, both of which were confirmed at the protein level. Our data indicate that mCRP is the more abundant form of CRP in human choroid, and that mCRP levels are elevated in individuals with the high‐risk CFH genotype. Moreover, pro‐inflammatory mCRP significantly affects endothelial cell phenotypes in vitro and ex vivo, suggesting a role for mCRP in choroidal vascular dysfunction in AMD. Copyright