Progression of Retinal Pigment Epithelial Alterations During Long-term Follow-up in Female Carriers of Choroideremia and Report of a Novel CHM Mutation

Abstract

To report clinical and functional findings in 2 female carriers of choroideremia who were followed up for 11 and 17 years and who showed progression of fundus alterations; and to report a novel CHM mutation. Methods: We performed follow-ups in 2 female carriers of choroideremia, including repeated clinical and electrophysiologic examinations and fundus autofluorescence. Molecular analysis of the CHM gene was done by direct sequencing of the coding exons. Results: Follow-up of female carrier 327 took place during 17 years. A second female carrier (subject 869) with a novel gene mutation in CHM was followed up for 11 years. The 2 carriers showed marked pigmentary alterations in the periphery of the retina. At the initial visit, carrier 869 had multiple small, yellowish flecks in the macula. Both carriers developed subnormal 30-Hz flicker responses on full-field electroretinography during follow-up, whereas electrooculography responses were normal. In both carriers, progression of fundus alterations was noted. Fundus autofluorescence images showed multiple small flecks with reduced autofluorescence. Conclusions: Over time, fundus alterations in female carriers of choroideremia are visible, and mild cone dysfunction might develop. Multiple yellowish flecks can exist in the macula. The typical mottled irregularity in fundus autofluorescence is a valuable diagnostic criterion that facilitates specific genetic testing. Clinical Relevance: Fundus alterations in female carriers of choroideremia can progress over time and a mild generalized cone dysfunction can develop. Characteristic irregularities are seen in fundus autofluorescence imaging, which is helpful in identifying female carriers of choroideremia.

Phenotyping Choroideremia and Its Carrier State With Multimodal Imaging Techniques

“…While most women carriers exhibit no visual impairment, the severity of findings can vary greatly, with occasional cases of severe retinal abnormalities likely due to unbalanced X-chromosome inactivation. 2–4 The mosaic pattern seen on retinal exam and multifocal ERG testing, even in asymptomatic carriers, is also attributed to random X-chromosome inactivation early in development, where variable expression of the mutated REP1 protein leads to patches of normal and mutated cells. 5, 6 …”

“…Renner et al similarly described a case with peripheral pigmentary stippling with regions of hypopigmentation on fundus exam, corresponding hyperfluorescent specks on FAF, and subtle RPE irregularities on horizontal OCT scans through the macula. 2 In particular, it is important for the clinician to distinguish these characteristic fundus findings in CHM carriers from other disease states that demonstrate salt-and-pepper retinopathy. While X-linked choroideremia carriers have subretinal flecks in a reticular pattern, ocular albinism carriers tend to have pigment mottling in a radial pattern, X-linked carriers of retinitis pigmentosa demonstrate a characteristic tapetal reflex, and congenital rubella show pigment mottling in the macula.…”

High-Resolution Adaptive Optics Retinal Imaging of Cellular Structure in Choroideremia

“…These findings agree with other reports of AF and visual function in choroideremia carriers. 33,34 Other features visible in choroideremia patients are viewed occasionally in images from carriers as well, though the frequency is greatly reduced. The left eye of choroideremia carrier 13030 had a single bubble-like feature visible in the AOSLO image at approximately 1 mm temporal.…”

Gyrate atrophy: clinical and genetic findings in a female without arginine-restricted diet during her first 39 years of life and report of a new OAT gene mutation

“…The FAF in choroideremia is altered at the whole fundus and shows a speckled pattern everywhere, even in areas where RPE looks normal in funduscopy, especially in young patients [37]. This difference in FAF helps in diagnosing gyrate atrophy versus choroideremia along with further differences like inheritance pattern and typical speckled FAF pattern in female carriers of choroideremia [37][38][39][40].…”