Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.

Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual's DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.

Visual sampling during walking in people with Parkinson's disease and the influence of environment and dual-task.

Visuospatial dysfunction may play a crucial role in gait disturbance in Parkinson's disease (PD), in particular how visual exploration of the environment is integrated into gait control. In this study, we tested the hypothesis that people with PD would visually sample their environment less frequently than controls when walking under different levels of environmental complexity and dual-task. We also explored associations between saccadic outcomes and clinical measures. Visual sampling (saccadic frequency) and gait were measured concurrently for 21 people with PD and 12 age-matched controls during a series of walking tasks using electrooculography (EOG) synchronised with 3D motion analysis (VICON). Participants walked under four environmental conditions during single and dual-task. Saccade frequency and task duration were measured. PD participants took longer to complete all tasks than controls (p =.004). Environment and dual-task impacted on saccadic frequency especially for PD. For both groups, saccadic frequency increased when approaching a turn compared with straight walking. Prior to turning, PD made less frequent early preparatory saccades than controls (p =.012). Under dual-task conditions, people with PD made less frequent saccades than controls when walking straight ahead (p =.040) and in preparation for a turn (p =.032). Increased saccadic frequency was related to poorer attention, cognition and spatial memory in controls and people with PD for single-task conditions but not dual-task conditions. Impaired visual sampling may contribute to the gait disorder in PD, especially when navigating through complex environments and when distracted.