Congenital Stationary Night Blindness: Mutation Update and Clinical Variability

Abstract

Congenital stationary night blindness (CSNB) represents a group of low vision disorders with abnormal retinal neurotransmission where patients can exhibit reduced visual acuity, impaired night vision, myopia, nystagmus, and strabismus. Patients with recessive forms of CSNB have mutations in genes which encode proteins that function in transmission of the visual signal from photoreceptors to on-bipolar neurons: CACNA1F (incomplete X-linked CSNB, iCSNB, CSNB2A), NYX (complete X-linked CSNB, cCSNB, CSNB1A), GRM6 and TRMP1 (complete autosomal recessive CSNB; ar-cCSNB, CSNB1B, and CSNB1C), and CAPB4 (incomplete autosomal recessive CSNB, ar-iCSNB, CSNB2B). In a cohort of 199 patients diagnosed clinically with CSNB, 112 for X-linked iCSNB, 73 for X-linked cCSNB, and 14 with ar-cCSNB, we have now identified a total of 116 unique mutations (65 unpublished) in 159 of these families. Of these mutations, 69 were in CACNA1F, 32 in NYX, seven in GRM6, and eight in TRMP1; none were identified in CAPB4. Interestingly, CACNA1F mutations were identified among patients originally diagnosed with X-linked incomplete CSNB (iCSNB or CSNB2), Åland island eye disease (AIED and AIED-like), and Åland eye disease (AED) suggesting that these conditions are the same genetic condition. While the majority of mutations are private, two exceptions are noteworthy: the CACNA1F founder mutation (c.3166dupC, exon 27) was consistently observed among individuals with a Dutch-German Mennonite ancestry; and a 24-bp deletion mutation in NYX, which results in the loss of the RACPAACA amino acids in the N-terminal Cys-rich region of nyctalopin, was detected in 12 North American Caucasian CSNB families. As yet, no mutations have been identified in 40 of our 199 CSNB patients (20%). Analysis of the clinical features of patients with the two forms of X-linked CSNB (CSNB1A and CSNB2A) shows that there was extensive phenotypic variability, with greater variability among features in patients with CSNB2A. The high success rate of detecting mutations in NYX and CACNA1F in our patient cohort supports the notion that X-linked CSNB is more common than the autosomal recessive form of CSNB. Together these findings indicate that CSNB is both genetically heterogeneous and clinically variable, and that patients require a comprehensive clinical assessment, family history, and genetic assessment for correct diagnosis.