Presentation of TRPM1-Associated Congenital Stationary Night Blindness in Children

Abstract

Importance: Congenital stationary night blindness (CSNB) implies a stable condition, with the major symptom being nyctalopia present at birth. Pediatric clinical presentation and the course of different genetic subtypes of CSNB have not, to our knowledge, been well described in the era of molecular genetic diagnosis.

Objective: To describe the presentation and longitudinal clinical characteristics of pediatric patients with molecularly confirmed TRPM1-associated complete CSNB (cCSNB).

Design, setting, participants: This study was conducted at the University of Iowa from January 1, 1990, to July 1, 2015, and was a retrospective, longitudinal case series of 7 children (5 [71.4%] female) with TRPM1-associated cCSNB followed up for a mean (SD) of 11.1 (2.8) years.

Main outcomes and measures: History, ophthalmologic examination findings, full-field electroretinogram (ffERG) results, full-field stimulus threshold testing results, Goldmann visual field results, optical coherence tomography results, and molecular genetic results were evaluated. Presenting symptoms and signs, the correlation of refractive error with electroretinography, and clinical evolution were analyzed.

Results: Seven patients (5 [71.4%] female) presented early in childhood with strabismus (n = 6 [86%]), myopia (n = 5 [71%]), and/or nystagmus (n = 3 [43%]). The mean (SD) age at presentation was 8 (4) months and for receiving a diagnosis by ffERG was 7.3 years, with molecular diagnosis at 9.7 years. The mean (SD) length of follow-up was 11 (2.8) years. The best-corrected visual acuity at the most recent visit averaged 20/30 in the better-seeing eye (range, 20/20-20/60). The mean (SD) initial refraction was -2.80 (4.42) diopters (D) and the mean refraction at the most recent visit was -8.75 (3.53) D (range, -4.00 to -13.75 D), with the greatest rate of myopic shift before age 5 years. Full-field electroretinogram results were electronegative, consistent with cCSNB, without a significant change in amplitude over time. No patient or parent noted night blindness at presentation; however, subjective nyctalopia was eventually reported in 5 of 7 patients (71%). The full-field stimulus threshold testing results were moderately subnormal (-29.7 [3.8] dB; normal -59.8 [4.0] dB). Goldmann visual field results were significant for full I-4e, but constricted I-2e isopter. Eight different mutations or rare variants in TRPM1 predicted to be pathogenic were detected, with 3 novel variants.

Conclusions and relevance: Children with TRPM1-associated cCSNB presented before school age with progressive myopia as well as strabismus and nystagmus (but not nyctalopia), with stable, electronegative ffERG results, mildly subnormal full-field stimulus threshold testing results, and a constricted I2e isopter on perimetry. These findings suggest that ffERG and cCSNB genetic testing should be considered for children who present with early-onset myopia, especially in the presence of strabismus and/or nystagmus, and that TRPM1-associated cCSNB is a channelopathy that may present without complaints of night blindness in childhood.

Figure 1.. Visual Acuity and Refractive Error

A, Change in logMAR best-corrected visual acuity in the better-seeing eye of patients from time of initial recognition acuity to most recent visit. B, Change in refractive error from initial examination to most recent visit. The dotted line represents the average myopic change of the entire cohort.

Figure 2.. Representative Composite of Imaging and Visual Function Studies for Patients With TRPM1-Associated Complete Congenital Stationary Night Blindness

A, Typical fundus appearance of a patient with TRPM1 mutations. The right eye demonstrates myopic fundus with tilting of the optic disc and a peripapillary crescent. These features were universal, and no patients had bone spicule–like pigmentation or arteriolar narrowing. B, Spectral-domain optical coherence tomography (OCT) of right eye of patient 5. Note the normal lamination pattern with preservation of the outer retinal layers and staphylomatous excavation of the overall contour. All OCTs were similar. C, Goldmann visual field results for patient 5. Patient 5 demonstrates a small central scotoma and constriction of the I2e isopter. The central scotoma was not uniformly present; however, constriction of the I2e isopter was present in 6 of 7 patients (85.7%) (eFigure 1 in the Supplement). Ok indicates that the area was tested and was within normal limits. D, Representative full-field electroretinography (ERG) waveforms of patient 5 at age 13 years compared with a normal ERG waveform. Note the electronegative standard combined response (dark-adapted [DA] 3.0), biphasic oscillatory potentials and flattened, broad a wave on light-adapted (LA) 3.0 bright flash (LA 3.0).

Figure 3.. Change in Electroretinogram for Each Individual Patient and Average for Cohort

A, Change in dark-adapted (DA) 3.0 b-wave amplitude (P = .90). B, Change in DA 3.0 b/a wave (P = .78). C, Change in light-adapted (LA) 3.0 b-wave amplitude (P =.07). D, Change in LA 30-Hz flicker response (P = .07). While the average change for the cohort was greatest for LA responses, it was not statistically significant.