Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity. We report here that six out of eight female probands with autosomal-recessive complete CSNB (cCSNB) had mutations in TRPM1, a retinal transient receptor potential (TRP) cation channel gene. These data suggest that TRMP1 mutations are a major cause of autosomal-recessive CSNB in individuals of European ancestry. We localized TRPM1 in human retina to the ON bipolar cell dendrites in the outer plexifom layer. Our results suggest that in humans, TRPM1 is the channel gated by the mGluR6 (GRM6) signaling cascade, which results in the light-evoked response of ON bipolar cells. Finally, we showed that detailed electroretinography is an effective way to discriminate among patients with mutations in either TRPM1 or GRM6, another autosomal-recessive cCSNB disease gene. These results add to the growing importance of the diverse group of TRP channels in human disease and also provide new insights into retinal circuitry.

Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(∗)) in PDE6H, encoding the inhibitory γ subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory γ subunit in cone phototransduction.

ABSTRACT.Purpose: To describe the outcome of specialized electrophysiology in visually impaired children. Methods: We carried out a retrospective evaluation of 340 electrophysiological examinations performed in 298 children over a 3-year period (2001)(2002)(2003), with regard to demographic data, referral pattern, degree of compliance, and diagnostic results. Electrophysiology was performed without sedation or anaesthesia. In electroretinograms, DTL electrodes were used in combination with online selection of responses. Visual evoked potentials testing was performed with seven active occipital electrodes. Results: The mean age of the children was 7 ± 5 years; 72 (24%) of the children were mentally as well as visually impaired. Main reasons for referral were suspected posterior segment disease, abnormal visual development, unexplained low vision, high myopia, and suspected albinism. Compliance was good in 302 ⁄ 340 (88%), partial in 24 ⁄ 340 (7%), and absent in 14 ⁄ 340 (4%) of the examinations. Of the 326 successful procedures, 215 (66%) showed abnormal results. Tapetoretinal dystrophy (22%), opticopathy (16%), congenital stationary night blindness (13%), and cone dystrophy (11%) were the most frequently established diagnoses. Albinism was confirmed in 14 of 24 suspected patients; additionally, unsuspected misrouting was found in six. In 26 (9%) of the patients, a previously established diagnosis was changed. Conclusions: In a specialized setting, electrophysiological examinations can be performed successfully in visually impaired children. The results are essential for the final ophthalmological diagnosis and have important consequences for rehabilitation.