Retinal axonal degeneration in Niemann–Pick type C disease

Abstract

Objective Niemann-Pick disease type C1 (NPC1) is a rare autosomal-recessive lysosomal storage disorder presenting with a broad clinical spectrum ranging from a severe infantile-onset neurovisceral disorder to late-onset neurodegenerative disease. Optical coherence tomography (OCT) is established to detect retinal degeneration in vivo. We examined NPC1-patients (NPC1-P), clinically asymptomatic NPC1-mutation carriers (NPC1-MC), and healthy controls (HC) to (1) identify retinal degeneration in NPC1-disease and (2) to investigate possible subclinical retinal degeneration in NPC1-MC. Methods Fourteen NPC1-P, 17 NPC1-MC, and 31 age-matched HC were examined using spectral-domain OCT. Neurological examinations, clinical scales [modified Disability Rating Scale (mDRS); Scale for the Rating and Assessment of Ataxia (SARA); Spinocerebellar Ataxia Functional Index (SCAFI)], and video-oculography (VOG) were correlated with OCT data. Results Macular retinal nerve fiber layer and volumes of combined ganglion cell and inner plexiform layer were significantly lower in NPC1-P compared to HC [mRNFL (µm):0.13 ± 0.01 vs. 0.14 ± 0.02; p = 0.01; GCIPL (mm 3):0.60 ± 0.05 vs. 0.62 ± 0.04; p = 0.04]. No significant differences were found in NPC1-MC in comparison to HC. In NPC1-P, the amplitude of upward vertical saccades showed positive associations with peripapillary RNFL (ρ = 0.645; p < 0.05), and thinned GCIP (ρ = 0.609; p < 0.05), but not in NPC1-MC. In NPC1-P correlations between combined outer plexiform layer and outer nuclear layer (OPONL) with mDRS (r = − 0.617; p < 0.05) and GCIP with SARA (r = − 0.622; p < 0.05) were observed. Furthermore, in NPC1-MC, motor scores were negatively associated with pRNFL (ρ = − 0.677; p < 0.01). Conclusions Using OCT, we showed retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements. We observed a non-significant trend of retinal degeneration in NPC1-MC correlating with subclinical motor abnormalities. Based on these preliminary data, OCT may be an important marker of neurodegeneration in NPC1-disease after onset of clinical symptoms.

Vertical saccadic palsy and foveal retinal thinning in Niemann-Pick disease type C

“…To the contrary we cannot support findings by Havla et al, who reported reduced volumes of macular NFL, as well as a thinner peripapillary RNFL, and combined GCL/IPL, compared to age- and sex-matched controls in their study. Of note, their patients exhibited reduced Snellen Visual Acuity Equivalent, while in our cohort almost all patients had normal visual acuity [ 14 ].…”

Cholesterol homeostasis in the vertebrate retina: biology and pathobiology

“…We will now specifically consider the mevalonate pathway in the RPE. While immunohistochemical analysis has shown the presence of HMGCR in human and murine RPE cells (61,80) imaging of the neural retina of NPC-1 patients has revealed significant thinning of the nerve fiber layer and axonal degeneration (112). Surprisingly, however, patients with lysosomal acid lipase (LAL) deficiency which results in accumulation of lysosomal cholesteryl esters do not exhibit retinopathies (113).…”

Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neuronsin vivo

“…Previous studies investigated how CD affected NPC animal models and patients after chronic administration for weeks to months (Aqul et al, 2011;Berry-Kravis et al, 2018;Farmer et al, 2019;Fukaura et al, 2021;Ory et al, 2017;Palladino et al, 2015;Praggastis et al, 2015;Vite et al, 2015), but the immediate effects of CD on brain cells remain unknown despite growing interest in CD-based therapies for other neurodegenerative diseases (Coisne et al, 2016). Here, we addressed this fundamental question using the retina as accessible part of the CNS that is affected by NPC1 dysfunction in humans (Havla et al, 2020;Palmer et al, 1985) and in animal models (Claudepierre et al, 2010;Palladino et al, 2015;Phillips et al, 2008;Yan et al, 2014a). For drug administration, we chose intravitreal injections that enable direct delivery of molecules to the retina and subsequent monitoring of drug effects at defined time points (Del Amo et al, 2017).…”