Evidence for impaired olfactory function and structural brain integrity in a disorder of ciliary function, Usher syndrome

Abstract

Diseases involving cilia dysfunction, such as Usher Syndrome (USH), often involve visual and auditory loss. Psychophysical evidence has suggested that this may also hold true for the peripheral olfactory domain. Here we aimed to go a step further by attempting to establish relations between the integrity of cortical structures and olfactory function in this condition. We investigated olfactory function for USH types 1 (USH1) and 2 (USH2). Bilateral olfactory bulb (OB) volume and olfactory sulcus (OS) depth were also analysed.Thirty-three controls with no previous olfactory deficits were age, sex and handedness-matched to 32 USH patients (11 USH1, 21 USH2). A butanol detection threshold test was performed to measure olfactory function. For OB volume and OS depth, morphometric measurements were performed using magnetic resonance imaging (MRI) based on detailed segmentation by three independent operators. Averaged values across these were used for the statistical analyses. Total intracranial volume was estimated using Freesurfer to account for head size variability.Olfactory threshold was significantly lower in controls when compared to USH, USH1, and USH2. OS depth was found to be shallower in both hemispheres in USH patients when compared with the control group. OB volume was not significantly different between control and USH groups, or respective subgroups. Nevertheless, butanol threshold was negatively correlated with the left OB volume for the USH type 1 subgroup. The main effect of OS depth reduction was found to be mainly due to the comparison between USH2 and controls.Our results provide evidence for morphometric changes and olfactory dysfunction in patients with USH. This correlated with a reduction in left OB volume in the USH1 subgroup, the most severe USH phenotype. The main effect of reduced OS depth was found to stem mainly from USH2 raising questions regarding a possible complex interaction between sensory olfactory loss and central cortical changes in this disease.

USH2A-retinopathy: From genetics to therapeutics

“…Although contradictory studies have been subsequently reported ( van Aarem et al, 1999 ), one study indicated cilia axoneme impairment in sperm as part of the Usher syndrome pathogenesis ( Hunter et al, 1986 ). Further evidence implicating Usher syndrome as a ciliopathy is the accelerated age-related olfactory decline reported among Usher patients ( Ramos et al, 2019 ; Ribeiro et al, 2016 ). Additionally, a recent study showed reduced ciliogenesis in USH2A patient-derived human dermal fibroblasts compared to a healthy control ( Samanta et al, 2019 ).…”

Anatomical and Functional Impacts of Congenital Bilateral Visual Deprivation on the Visual Pathway—A Comprehensive Review

“…Moreover, psychophysical assessments have revealed a consistent olfactory loss in USH [ 50 ]. A study on brain structural integrity also found that the olfactory sulcus was shallower in USH patients compared to the control group [ 52 , 53 ].…”

Decreased activity of piriform cortex and orbitofrontal hyperactivation in Usher Syndrome, a human disorder of ciliary dysfunction

“…Moreover psychophysical assessment reveals consistent olfactory loss in USH (Ribeiro et al, 2016 ). A study on brain structural integrity also showed that the olfactory sulcus was shallower in USH patients when compared with the control group (Ramos et al, 2019 ). Studies in mice have also provided evidence for USH olfactory impairment (Jansen et al, 2016 ; Sahly et al, 1997 ; Wolfrum et al, 1998 ).…”