Audo et al. (2014) examined 9 affected members of a large 3-generation family segregating an autosomal dominant form of inner retinal dystrophy with ganglion cel...
Audo et al. (2014) examined 9 affected members of a large 3-generation family segregating an autosomal dominant form of inner retinal dystrophy with ganglion cell abnormalities. Onset of symptoms was between 25 and 40 years of age. Light sensitivity was the first sign, reported by all subjects, followed by progressive loss of central vision. Visual acuity varied from 20/25 to 20/400 (average, 20/50). Visual fields showed decreased central retinal sensitivity with preservation of peripheral visual field. There were macular changes, optic disc pallor, and hyperreflectivity of ganglion cell and nerve fiber layers, with loss of optic nerve fibers. Full-field electroretinography (ERG) showed inner retinal (postreceptor) dysfunction in all cases, with absent or very reduced b-waves but normal a-waves under scotopic conditions. Oscillatory potentials were reduced in amplitude with a simplified wave shape in younger patients and were undetectable in older patients, consistent with inner retinal dysfunction. Long-duration stimulation recordings suggested both ON and OFF pathway dysfunction, and pattern ERG revealed reduced amplitude for both P50 and N95 components, consistent with proximal macular dysfunction. None of the affected individuals had systemic disease, and there was no family history of dementia; specifically, all examined individuals were temporally and spatially oriented, and Mini-Mental State Examination was normal in the 50-year-old proband.
The transmission pattern of retinal dystrophy in the family reported by Audo et al. (2014) was consistent with autosomal dominant inheritance.
▼ Molecular Genetics
In a large 3-generation family segregating autosomal dominant retinal dystrophy, in which analysis of all known genes implicated in retinal diseases did not reveal any pathogenic variants segregating with disease, Audo et al. (2014) performed whole-exome analysis and identified a missense mutation in the ITM2B gene (E261A; 603904.0003). The mutation, which segregated with disease in the family, was not found in 380 control alleles. Haplotype analysis of 19 family members identified a 24.6-Mb interval on chromosome 13q that included ITM2B and cosegregated in affected individuals; sequencing of 74 genes in that interval revealed no variants that cosegregated with disease except for E261A in ITM2B.