Disease progression in autosomal dominant cone-rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene

Abstract

Purpose: To document longitudinal fundus autofluorescence (FAF) and electroretinogram (ERG) findings in a family with cone-rod dystrophy (CRD) caused by a novel missense mutation (D100G) in the GUCA1A gene.

Methods: Observational case series.

Results: Three family members 26-49 years old underwent complete clinical examinations. In all patients, funduscopic findings showed intraretinal pigment migration, loss of neurosensory retinal pigment epithelium, and macular atrophy. FAF imaging revealed the presence of a progressive hyperautofluorescent ring around a hypoautofluorescent center corresponding to macular atrophy. Full-field ERGs showed a more severe loss of cone than rod function in each patient. Thirty-hertz flicker responses fell far below normal limits. Longitudinal FAF and ERG findings in one patient suggested progressive CRD. Two more advanced patients exhibited reduced rod response consistent with disease stage. Direct sequencing of the GUCA1A gene revealed a new missense mutation, p.Asp100Gly (D100G), in each patient.

Conclusion: Patients with autosomal dominant CRD caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG characteristics and subsequent genetic testing.

Figure 1

(a) Atrophic macula in P1, the proband, age 49, (OD) with normal surrounding retina. Migrated retinal pigment epithelium (white arrows) localized around areas of exposed choroidal vessels. (b) Similar atrophic findings (OS) in P1. (e, f) Corresponding fundus autofluorescence (FAF) images in the eyes (OU) of P1. Dark central atrophy is enclosed within a ring of high density autofluorescence. Massive depositions of hyperautofluorescent material is observed in the infero-temporal region of the lesions in both eyes. (c) P2, age 51, exhibiting similar features including RPE migration and abnormally extensive choroidal vessel visibility. (g) An increased signal of AF surrounds a lesion of dark atrophy resembling that of the proband, P1, along with a granular RPE appearance in the infero-temporal region of the macula. (d) P3, age 26, exhibited milder symptoms when compared to the more advanced P1 and P2. Early RPE migration (white arrows) and pigmentation was detected along darkening area of retinal thinning. (h) A band of AF, extending temporally is observed surrounding an area of early atrophy and hypoautofluorescence.

Figure 2

Serial fundus autofluorescence imaging in P3. A three-year follow-up visit shows the expansion of early atrophy (turquoise arrows) in the macula as well as spatial increases in autofluorescence (white arrows). Images taken at the first visit (a, c for RE and LE, respectively) were compared to images taken three year later (b, d for RE and LE respectively) to document disease progression.

Figure 3

The International Society for Clinical Electrophysiology of Vision (ISCEV)-standardized scotopic rod, maximal, 30 Hz flicker, and photopic cone responses of the rights eyes of P1, P2, and P3. An average scan (black), along with a successive typical responses (red), is shown for each stimulus condition. Normal waveforms for a subject (age 20–50) are provided in the bottom row for each condition. Note the adjustment in the amplitude scale for the 30 Hz flicker and photopic cone stimuli in P1, P2, and P3, revealing severe waveform and amplitude attenuation.

Figure 4

Quantitative ERG results for each patient and their respective age-match normal ranges are plotted to show relative measurements in amplitude and implicit time differences. N(1,2) represents the normative age range for P1 and P2 (age 50–60) and N(3) for P3 (age 20–30) – asterisks (*) mark significant deviations from normal ranges in each plot. All patients exhibited extinguished b- and a-wave forms of the 30 Hz flicker and photopic cone responses; however, only P2 and P3 exhibited implicit time delays for these stimuli while P1 showed relative sparing of photopic implicit time. Scotopic rod responses were borderline normal in amplitude for both P1 and P2, but the implicit time was prolonged only for P2.

Figure 5

ERG responses for patient 3 from 2009 (left panel) and 2012 (right panel) (RE: dark gray, LE: light gray lines) showing the disease progression.