Family 1 (GC17489) was previously investigated and a pathogenic variant c.121C>T, p.Arg41Trp in
CRX was identified in individual III:3 and his asymptomatic mother (findings reported previously by Hull et al.
20). Owing to the unusual clinical presentation in III:3 and the nonsegregating optic atrophy and distinct phenotype in III:2, the
CRX variant was thought to not account for the full phenotype and thus the family was recruited into the 100KGP for further investigation. Individual III:2 was noticed to have vision problems on routine screening at the age of 3 years. At that time, she was diagnosed with bilateral optic atrophy. Her vision significantly deteriorated from the age of 11 years. Later, at the age of 18 to 19 years, she started to experience muscle fatigue, weakness, and intermittent vertigo, which was accompanied by nausea. She also complained of a burning sensation in her hands and feet. At the age of 23 years, she was diagnosed with postural orthostatic tachycardia syndrome. Fundus examination revealed severe bilateral optic atrophy, retinal vessel attenuation, and abnormal foveal reflex. Spectral domain optical coherence tomography (SD-OCT) imaging showed thinning of the retinal nerve fiber layer, retinal ganglion cell (RGC) layer and ellipsoid zone disruption within the fovea region (
Fig. 3). Visual electrophysiology at the age of 13 years showed profoundly delayed pattern VEP waveforms that were broadened in shape (peak times of 140 ms on the right and 160 ms on the left; upper limit of reference range, 115 ms). The PERG P50 component was of normal amplitude, excluding a macular cause of pattern VEP abnormality, but P50 was of abnormally short peak time and the N95:P50 ratio subnormal bilaterally, consistent with severe RGC dysfunction bilaterally (
Fig. 4). Full-field ERGs were normal, revealing no evidence of generalized rod or cone system dysfunction. Repeat testing at the age of 26 years indicated attenuation of PERG P50, but with a further shortening of peak times bilaterally; pattern VEPs were undetectable, in keeping with progression of optic nerve/RGC dysfunction (
Fig. 4). Repeat full-field ERGs were normal. Her father (II:3), 46 years of age at the time of the initial examination, was asymptomatic. His best-corrected visual acuity (BCVA) was 6/12 in the right eye and 6/9 in the left eye. His electrophysiology assessment showed pattern reversal VEPs with a positive peak that was within normal timing limits, but indicated borderline delay on the left compared with the right eye; amplitudes were just within normal limits. The PERG showed abnormalities including a short P50 peak time and subnormal N95:P50 ratio on the right and peak time that was borderline on the left (
Fig. 4). There was evidence to suggest additional mild bilateral P50 reduction related to optical factors. Full-field ERGs were normal. At the age of 54 years, his visual function assessment was repeated. His visual acuity remained stable and he was able to read 16/17 and 17/17 Ishihara color tests plates. Visual field testing was within normal limits (data not shown). Fundus examination was within normal limits; however, SD-OCT imaging revealed thinning of the RGC layer (
Fig. 5) and disruption of the ellipsoid zone bilaterally (
Fig. 3). His repeat visual electrophysiology at the age of 52 years, including ERG, was largely stable, with the exception of a mild shortening of P50 peak time on the left (
Fig. 4). These findings suggested bilateral RGC dysfunction, without VEP evidence of optic nerve conduction delay. The index patient's affected brother (III:3) was noticed to have nystagmus and reduced visual acuity at the age of 3 years. At that time, his visual electrophysiology assessment showed delayed flash VEPs and evidence of rod–cone dysfunction on ERG. In addition, he was noticed to have delayed speech and some learning difficulties at secondary school. Over the years, he developed intention tremor and unexplained vertigo, for which he was investigated extensively. He reports that stressful stimuli may lead to fainting, during which he experiences fits. His fundus examination revealed severe bilateral optic atrophy, severe retinal vessel attenuation, mild pigmentary changes, and RPE atrophy. SD-OCT imaging showed significantly reduced retinal thickness. Fundus imaging is available in a previous publication by Hull et al.
20