Retinal phenotypes and longitudinal clinical courses in patients with NPHP1-associated Senior-Løken syndrome

This study aimed to describe retinal phenotype, longitudinal clinical course, and genetic findings in Japanese patients with NPHP1-associated Senior-Løken syndrome and their siblings.

Retrospective, multicenter case series.

This study included 12 patients with biallelic pathogenic NPHP1 variants, comprising 10 probands with symptomatic retinal dystrophy recruited from six ophthalmic centers across Japan and 2 affected siblings identified through family screening. Clinical and genetic findings were analyzed. Retinal dystrophy was diagnosed using fundus photography, fundus autofluorescence (FAF), optical coherence tomography, and electroretinography. Genetic testing was performed using whole-exome and/or whole-genome sequencing. Follow-up ranged from 0 to 44 years (mean, 14.6 years).

Retinal phenotype, onset of retinopathy and nephropathy, and genotype.

Retinal phenotypes included cone/cone-rod dystrophy (4 patients), retinitis pigmentosa (4 patients), sector retinitis pigmentosa (2 patients), pigmented paravenous retinochoroidal atrophy (1 patient), and normal retina (1 patient). FAF images showed a descending tract in 5 patients. Retinopathy preceded nephropathy in 9 patients, all of whom were initially diagnosed with Leber congenital amaurosis or early-onset retinal dystrophy. Genetic testing showed that 11 patients harbored a homozygous whole-NPHP1 deletion, whereas 1 carried compound heterozygous NPHP1 and EYS variants.

Patients with NPHP1-associated Senior-Løken syndrome showed considerable inter- and intrafamilial variability in retinal phenotype. Pigmented paravenous retinochoroidal atrophy can be associated with NPHP1 variants. A descending tract on FAF imaging may be a characteristic feature of retinal degeneration in Senior-Løken syndrome. Retinopathy, which commonly manifests as Leber congenital amaurosis or early-onset retinal dystrophy, often precedes nephropathy in patients with NPHP1-associated Senior-Løken syndrome.