Analysis of retinal function and structure in autosomal recessive retinal-renal ciliopathy

To the Editor:

Cilia are finger-like projections that are present in specialised cells in several organs including the kidney tubules and the retina. In the latter, a ciliary structure termed the connecting cilium connects the inner and outer segments of the rods and cones [1]. The connecting cilium is essential for photoreceptor function and contains several proteins that are encoded by genes incriminated in retinal dystrophies. Recently this structure has been made indirectly observable in vivo as a hyperreflective line in the outer retina, the inner segment ellipsoid (ISe) line, using high resolution spectral domain optical coherence tomography. It is believed that the densely packed mitochondria, required for the transport of molecules and energy production needed for the daily outer segment disc renewal, are the main source of the hyperreflectivity that constitutes the ISe. As cilia in different organs share common structural proteins that are encoded by the same genes, mutations which encode these structural proteins can affect ciliary structures in multiple organs. One example is retinal-renal ciliopathy syndrome, Senior Loken syndrome (SLS, OMIM 266900) [2, 3]. So far, mutations in 13 genes are known to cause nephronophthisis, nine of which are also considered to lead to retinal degeneration [4]. Two such genes are NPHP4 (OMIM #606966) and NPHP5 (IQCB1) (OMIM #609237). Although their exact function is not known, NPHP4 and NPHP5 are believed to interact with multiple proteins in the transition zone or base of cilium, including with the Retinitis GTPase Regulator (RPGR) and RPGR-Interacting Protein 1 (RPGRIP1), an interaction which may explain the mechanism of retinal degeneration in patients with mutations in these genes. We speculate that this ciliary structure might be affected early on in SLS, and may serve as a marker of the disease.

Five patients (age range 6–42 years) with SLS were identified through a retrospective review of patient encounters and a search of a retinal dystrophy registry including 789 patients, leading to an estimated prevalence of <1% of SLS among retinal dystrophies. All patients came from consanguineous families. The full-field electroretinogram was non-recordable in all except in Patient 3 in whom both scotopic and photopic responses were severely reduced (Table 1). Two novel likely disease causing mutations were detected (Table 1). The retinal phenotype was similar in all patients, including severe central and peripheral degeneration (Fig. 1). Patients 1 and 2 presented with a history of nephronophthisis, while all other patients had normal renal function. The complete syndrome including nephronophthisis may not always be fully penetrant. This variability is believed to be caused by factors such as the complexity of interaction of several of the gene products in the cilia, tissue-specific posttranslational modification and alternative tissue-specific splicing. In conclusion, macular dysfunction and macular structural changes including loss of the ISe were present in all patients with SLS, consistent with ciliopathy. On the other hand, ISe affection can occur in multiple other acquired and hereditary retinal conditions [5]. Assessment of the ISe line may be a surrogate endpoint in future clinical trials on gene therapy for SLS.

Table 1 Retinal function and structure and pathogenetic mutations in five patients with Senior Loken Syndrome.

Fig. 1: Multimodal retinal imaging in Senior-Loken syndrome.

Upper panel. Wide field fundus imaging of a 42-year-old female with a novel compound heterozygous c.563C>A missense mutation and a previously described c.1880C>T missense mutation in NPHP4 (Patient 3). Middle panel. Fundus autofluorescence imaging with enlarged macular hypoautofluorescent area corresponding to the maculopathy. Lower panel. Spectral domain optical coherence tomography shows absence of inner segment ellipsoid (ISe) in the macular area.