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Hardcastle et al. (2000) studied a 5-generation family with an atypical form of retinitis pigmentosa (RP) in which onset of vision loss in males was unusually ea...

Hardcastle et al. (2000) studied a 5-generation family with an atypical form of retinitis pigmentosa (RP) in which onset of vision loss in males was unusually early, before 2 years of age, and female obligate carriers had normal fundi and waveforms. The proband presented with limited central vision and poor night vision at age 2 years. Upon examination he was able to fix and follow with both eyes; funduscopy showed abnormal grayish macular reflexes and extensive whitish-gray spots throughout the midperiphery of the posterior pole with some areas of coalescence. Examination at 6 years of age revealed eccentric fixation, with visual acuities in the 20/800 range; funduscopy was unchanged except for evidence of retinal arteriole attenuation. At 11 years of age, the boy's visual acuity was limited to counting fingers at 2 to 3 feet and he had markedly constricted peripheral vision; changes in the retinal pigment epithelium (RPE) were nearly confluent in the midperiphery, with small areas of atrophy and a few small patches of intraretinal pigment; retinal arterioles were clearly attenuated in all quadrants, without optic nerve pallor. The proband's maternal uncle was examined at age 21 years and had nondetectable electroretinography (ERG) recordings bilaterally, abnormal color vision, and only residual temporal and inferior fields of vision. Funduscopic examination showed absence of foveal reflexes bilaterally, diffuse granularity of the RPE in the central macula, and moderate intraretinal pigment in the midperiphery. At 35 years of age, visual acuity had deteriorated to hand motion for both eyes, with relatively unchanged fundi except for more notable areas of RPE atrophy and increased amounts of intraretinal pigment in the periphery. In addition, posterior subcapsular cataracts were now detected. The proband's mother and maternal grandmother, both obligate carriers for the condition, had completely normal funduscopic examinations and normal waveforms on ERG.

▼ Mapping
By haplotype and linkage analysis in a family segregating retinitis pigmentosa, Hardcastle et al. (2000) found linkage of the disorder to a locus on Xp22, which they designated RP23. Recombination events narrowed the critical interval to an approximately 15-cM region between markers DXS1223 and DXS7161 at Xp22.32-p22.13. The authors stated that disease in this family was clinically distinct from that described by McGuire et al. (1995) (see RP3, 300029) and segregated with more distal markers on chromosome Xp.

▼ Molecular Genetics
In the proband from the 5-generation family with X-linked retinitis pigmentosa previously studied by Hardcastle et al. (2000), Webb et al. (2012) performed targeted genomic next-generation sequencing for the entire RP23 disease interval and identified an intronic variant in the OFD1 gene (300170.0011) that segregated with disease in the family and was not found in 220 control chromosomes. Screening for the intronic OFD1 mutation in 11 unrelated male patients with X-linked RP, in whom mutation in the RPGR (312610) and RP2 (300757) genes had previously been excluded, did not detect the variant.

Exclusion Studies

In a 5-generation family with retinitis pigmentosa mapping to chromosome Xp22.32-p22.13, Hardcastle et al. (2000) sequenced the candidate gene RS1 (300839) but found no mutations.

Tags: Xp22.2