Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy-A Case Report

Abstract

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α_1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype-phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors.

Keywords: AIED; Aland island eye disease; CACNA1F; Cav1.4; retinoschisis.

Figure 1

The color fundus images of the right (A) and the left (B) eye.

Figure 2

Optical coherence tomography (OCT) scan of the right macula revealed retinoschisis (A), whereas foveal hypoplasia was visible in the left eye (B).

Figure 3

Flash full-field electroretinogram (ffERG) characteristics in control subject (A); patient with CSNB type 1, complete (CSNB1) (B); index patient with Aland Island eye disease (AEID) (C). DA 0.01—dark-adapted 0.01 ERG (rod response); DA 3.0—dark-adapted 3.0 ERG (combined rod-cone response); LA 3.0—light-adapted 3.0 ERG (single-flash cone response); LA 3.0 flicker—light-adapted 3.0 flicker ERG (30 Hz flicker, cone response); On-Off—On-Off ERG (bipolar cell response).

Figure 4

Schematic presentation of the Cav1.4 channel that is composed of a main pore-forming α₁ subunit and auxiliary β and α₂δ₄ subunits. Cav1.4α₁ subunit is a single peptide chain composed of four similar domains (I–IV), each repeat contains six transmembrane helices (named S1–S6) linked by intracellular loops between the S5 and S6 segments. Helices S1–S4 of each repeat act as the voltage sensing domain (VSD). Helices S5–S6 of the four repeats with their connecting linker comprise the ion-conducting pore, which permit ions to flown down the electrochemical gradient from the extracellular milieu into the cytoplasm. In the distal end of the C-domain, the autoinhibitory domain is located [16]. In the index patient, the mutation involved the extracellular region between IV-S5 and IV-S6 and an insertion of a premature stop codon altered membrane topology for the C-terminal part of the protein.