Elsevier

Ophthalmology

Volume 120, Issue 10, October 2013, Pages 2072-2081
Ophthalmology

Original article
Genotype and Phenotype of 101 Dutch Patients with Congenital Stationary Night Blindness

https://doi.org/10.1016/j.ophtha.2013.03.002Get rights and content

Objective

To investigate the relative frequency of the genetic causes of the Schubert–Bornschein type of congenital stationary night blindness (CSNB) and to determine the genotype-phenotype correlations in CSNB1 and CSNB2.

Design

Clinic-based, longitudinal, multicenter study.

Participants

A total of 39 patients with CSNB1 from 29 families and 62 patients with CSNB2 from 43 families.

Methods

Patients underwent full ophthalmologic and electrophysiologic examinations. On the basis of standard electroretinograms (ERGs), patients were diagnosed with CSNB1 or CSNB2. Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in NYX, TRPM1, GRM6, and GPR179 in patients with CSNB1 and CACNA1F and CABP4 in patients with CSNB2.

Main Outcome Measures

Data included genetic cause of CSNB, refractive error, visual acuity, nystagmus, strabismus, night blindness, photophobia, color vision, dark adaptation (DA) curve, and standard ERGs.

Results

A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Mutations causing CSNB1 were found in NYX (20 patients, 13 families), TRPM1 (10 patients, 9 families), GRM6 (4 patients, 3 families), and GPR179 (2 patients, 1 family). Congenital stationary night blindness 2 was primarily caused by mutations in CACNA1F (55 patients, 37 families). Only 3 patients had causative mutations in CABP4 (2 families). Patients with CSNB1 mainly had rod-related problems, and patients with CSNB2 had rod- and cone-related problems. The visual acuity on average was better in CSNB1 (0.30 logarithm of the minimum angle of resolution [logMAR]) than in CSNB2 (0.52 logMAR). All patients with CSNB1 and only 54% of the patients with CSNB2 reported night blindness. The dark-adapted threshold was on average more elevated in CSNB1 (3.0 log) than in CSNB2 (1.8 log). The 3 patients with CABP4 had a relative low visual acuity, were hyperopic, had severe nonspecific color vision defects, and had only 1.0 log elevated DA threshold.

Conclusions

Congenital stationary night blindness 1, despite different causative mutations, shows 1 unique CSNB1 phenotype. Congenital stationary night blindness 2 caused by mutations in CABP4 merely shows cone-related problems and therefore appears to be distinct from CSNB2 caused by mutations in CACNA1F.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Study Population

Patients were referred to Bartiméus by ophthalmologists from hospitals across The Netherlands. Reasons for referral included reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age. All patients were Caucasian. On the basis of standard ERG measurements as recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV),22 the patients were diagnosed with CSNB1 or CSNB2. The age of the patients at the time of the ERG was on

DNA Analysis in Patients with CSNB1 and Patients with CSNB2

Figure 2 shows the distribution of the molecular genetic cause of our population of 39 patients with CSNB1 (from 29 families) and 62 patients with CSNB2 (from 43 families). To date, we have found a mutation in 94 patients (93%). In these 94 patients, the genetic diagnosis confirmed the electrophysiologically established diagnosis of CSNB1 or CSNB2. We did not find a mutation in 3 patients with CSNB1 (3 families) and 4 patients with CSNB2 (4 families). The mutations and the frequency of the

Discussion

We diagnosed 39 patients with CSNB1 and 62 patients with CSNB2 on the basis of clinical symptoms and standard ISCEV ERG measurements. Subsequent DNA analysis showed that the NYX (51%) and TRPM1 (26%) genes were the major causes of CSNB1,13 and that X-linked and autosomal recessive inheritance occurred equally in CSNB1 (Fig 2). In contrast, X-linked inheritance was predominant in CSNB2 (89%). The inheritance frequencies hardly changed when based on families instead of individual patients,

Acknowledgments

The authors thank C. C. W. Klaver and J. W. R. Pott for referring patients, and F. P. M. Cremers and K. W Littink for contributions in study design and technical assistance in DNA analysis.

References (32)

  • P. Lachapelle et al.

    The photopic electroretinogram in congenital stationary night blindness with myopia

    Invest Ophthalmol Vis Sci

    (1983)
  • K. Bradshaw et al.

    A comparison of ERG abnormalities in XLRS and XLCSNB

    Doc Ophthalmol

    (2004)
  • Y. Miyake et al.

    Characteristic ERG-flicker anomaly in incomplete congenital stationary night blindness

    Invest Ophthalmol Visual Sci

    (1987)
  • W.G. Pearce et al.

    Variable expressivity in X-linked congenital stationary night blindness

    Can J Ophthalmol

    (1990)
  • L.E. Allen et al.

    Genotype-phenotype correlation in British families with X linked congenital stationary night blindness

    Br J Ophthalmol

    (2003)
  • C.M. Pusch et al.

    The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein

    Nat Genet

    (2000)
  • Cited by (0)

    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    This study was partially funded by ODAS Stichting and Inzicht. The sponsor or funding organization had no role in the design or conduct of this research.

    View full text