A NOVEL CASE SERIES OF NMNAT1-ASSOCIATED EARLY-ONSET RETINAL DYSTROPHY: EXTENDING THE PHENOTYPIC SPECTRUM

To report two siblings with NMNAT1-associated retinopathy presenting with a later onset and milder phenotype than previously described.

Retrospective case series of two siblings. The authors describe two cases of early-onset retinal dystrophy caused by disease-causing NMNAT1 variants. Visual acuity, clinical examination, and retinal imaging including color fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence were performed. Both cases underwent full-field and pattern electroretinography incorporating the International standards.

Two siblings were found to harbor the variants c.53A>G, p.(Asn18Ser) and c.769G>A, p.(Glu257Lys) in NMNAT1 after retinal dystrophy panel gene testing. Both had good visual acuity until the ages of 6 and 11 years, respectively, with subsequent gradual worsening into their twenties. At the ages of 10 and 16 years, respectively, electroretinograms indicated generalized rod and cone system dysfunction of moderate severity, with pattern electroretinography evidence of severe macular involvement. Repeat testing at the ages of 26 and 33 years revealed only mild worsening of rod photoreceptor function in both.

NMNAT1-associated retinopathy has previously only been described as a typical form of Leber congenital amaurosis, with poor visual acuity from birth associated with nystagmus, characteristic macular atrophy, and intraretinal pigmentation from birth. Here, we present two siblings with a novel, later onset, and far milder phenotype. We suggest that this may be due to the two missense NMNAT1 variants resulting in milder reduction of NMNAT1 enzymatic activity. These cases extend the phenotypic spectrum associated with NMNAT1 and further highlight the clinical heterogeneity associated with inherited retinal diseases.