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Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.

Key points A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. Abstract It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

The cerebellum adapts motor responses by controlling the gain of a movement, preserving its accuracy and by learning from endpoint errors. Adaptive behavior likely acts not only in the motor but also in the sensory, behavioral, and cognitive domains, thus supporting a role of cerebellum in monitoring complex brain performances. Here, we analyzed the relationship between saccade latency, duration and endpoint error of antisaccades in a group of 10 idiopathic cerebellar atrophy (ICA) patients compared to controls. The latency distribution was decomposed in a decision time and a residual time. Both groups showed a trade-off between duration and decision time, with a peak of entropy within the range of this trade-off where the information flow was maximized. In cerebellar patients, greater reductions of duration as the time of decision increased, were associated with a lower probability for a saccade to fall near the target, with a constant low entropy outside the optimal time window. We suggest a modulation of saccade duration, depending on the latency-related decision time (accumulation of sensory and motor evidences in favor of a goal-directed movement), normally adopted to perform efficient trajectories in goal-directed saccades. This process is impaired in cerebellar patients suggesting a role for the cerebellum in monitoring voluntary motor performance by controlling the movement onset until the ambiguity of planning is resolved.

The knowledge of the visual strategies adopted while walking in cognitively engaging environments is extremely valuable. Analyzing gaze when a treadmill and a virtual reality environment are used as motor rehabilitation tools is therefore critical. Being completely unobtrusive, remote eye-trackers are the most appropriate way to measure the point of gaze. Still, the point of gaze measurements are affected by experimental conditions such as head range of motion and visual stimuli. This study assesses the usability limits and measurement reliability of a remote eye-tracker during treadmill walking while visual stimuli are projected. During treadmill walking, the head remained within the remote eye-tracker workspace. Generally, the quality of the point of gaze measurements declined as the distance from the remote eye-tracker increased and data loss occurred for large gaze angles. The stimulus location (a dot-target) did not influence the point of gaze accuracy, precision, and trackability during both standing and walking. Similar results were obtained when the dot-target was replaced by a static or moving 2D target and “region of interest” analysis was applied. These findings foster the feasibility of the use of a remote eye-tracker for the analysis of gaze during treadmill walking in virtual reality environments.

A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders.It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

s / Gait & Posture 42S (2015) S1–S27 S3 Table 1 Morphological and structural features in CP and TD children. Age [years] Muscle volume [cm3] Muscle length [cm] MTU [cm] Average muscle area [cm2] Normalized Muscle volume [cm2] Mean EI of muscle CP 8.6±2.3 32.4±13.8 16.2±3.9 33.5±6.0 2.1±0.5 1.1±0.3 101.0±9.7 TD 9.2±2.3 52.2±19.0 17.3±2.7 34.0±4.9 2.9±0.7 1.5±0.4 129.2±20.3 t-Test (p-value) 0.740 0.103 0.331 0.566 0.018* 0.040* 0.006* volume (=volume/MTU length) were calculated. In addition, the mean EI value (expressed in a grey-scale of 256 values), was also evaluated. Comparisons were made using the Student t-test (unpaired). Statistical significance (*) was set to p 0.79, p>0.01), but with a lower slope in CP (5.2 vs. 7.8 cm3/years). In CP, a significant negative correlation was found between EI and average muscle area (R2 =0.60, p=0.04). Discussion: We found a smaller muscle volume in CP children, as previously reported [2]. Interestingly, as a CP child ages, slower muscle growth occurs than in the TD children. Averaged muscle area was found to be more sensitive to distinguish between TD and CP children. Furthermore, the MG was hyper-echoic in the CP group relative to the TD group, supporting our hypothesis. Combining EI and average muscle area shows potential in estimating the amount of fibrotic changes occurring within a muscle. Utilising the new approach for 3D reconstruction offers an objective and efficient manner to diagnose muscle and tendon morphological and structural changes in the clinical environment.