BackgroundChronic neuronopathic Gaucher’s disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3.ObjectiveTo characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique.MethodsHorizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41.1 ± 11.0 years; modified severity scoring tool (mSST): 9.3 ± 5.4; Montreal Cognitive Assessment (MoCA): 24.0 ± 4.2] and age-matched controls were analyzed using EyeBrain T2, a head-mounted binocular eye tracker. Systematic clinical assessment included the mSST, a valid tool for monitoring the neurological progression in GD3 and MoCA.ResultsIn Norrbottnian GD3 patients, gain, peak, and average velocity (107.5°/s ± 41.8 vs. 283.9°/s ± 17.0; p = 0.0009) of horizontal saccades were reduced compared to healthy controls (HCs). Regarding vertical saccades, only the average velocity of downward saccades was decreased (128.6°/s ± 63.4 vs. 244.1°/s ± 50.8; p = 0.004). Vertical and horizontal saccadic latencies were increased (294.3 ms ± 37.0 vs. 236.5 ms ± 22.4; p = 0.005) and the latency of horizontal reflexive saccades was correlated with the mSST score (R2 = 0.80; p = 0.003). The latency of antisaccades showed association to MoCA score (R2 = 0.70; p = 0.009). GD3 patients made more errors in the antisaccade task (41.5 ± 27.6% vs. 5.2 ± 5.8%; p = 0.005), and the error rate tended to correlate with the cognitive function measured in MoCA score (p = 0.06).ConclusionThe mean age of 41 years of our GD3 cohort reflects the increased life expectancy of patients in the Norrbottnian area compared to other GD3 cohorts. Marked impairment of horizontal saccades was evident in all patients, whereas vertical saccades showed distinct impairment of downward velocity. Latency of reflexive saccades was associated with the severity of neurological symptoms. Increased latency and error rate in the antisaccade task were linked to cognitive impairment. The assessment of saccades provides markers for neurological and neuropsychological involvement in Norrbottnian GD3.
Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI). Female FMR1 premutation carriers rarely develop motor features. Dual pathology is an emerging phenomenon among FMR1 premutation carriers. Here, we describe a family affected by FMR1-related disorders in which the female index case has developed a rapidly progressive and disabling syndrome of atypical parkinsonism. This syndrome consists of early onset postural instability, echolalia, dystonia, and varying types of apraxia like early onset orobuccal apraxia and oculomotor apraxia. She has also developed supranuclear gaze palsy, increased latency of saccade initiation, and slow saccades. These features are compatible with progressive supranuclear palsy (PSP) of a corticobasal syndrome (CBS) variant. Imaging displays a marked reduction of presynaptic dopaminergic uptake and cerebrospinal fluid analysis showed reduced dopamine metabolism; however, the patient is unresponsive to levodopa. Midbrain atrophy ("hummingbird sign") and mild cerebellar atrophy were found on brain MRI. Her father was affected by a typical FXTAS presentation but also displayed dopamine deficiency along with the hummingbird sign. The mechanisms by which FMR1 premutations predispose to atypical parkinsonism and dopamine deficiency await further elucidation.
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