9 General introduction The common pathological feature of HSP is a retrograde axonal degeneration of the corticospinal tracts, posterior spinal columns, and, to a lesser extent, the spinocerebellar fibers.4 This degeneration may be due to e.g. abnormal membrane trafficking, axonal development, or mitochondrial functioning.13 To date, up to 87 genetic subtypes associated with HSP have been identified. The different genetic forms are assigned spastic paraplegia loci (SPG) based on sequential numbering in the order of discovery (e.g., SPG4, SPG8). Autosomal dominant, autosomal recessive, X-linked and mitochondrial modes of inheritance have all been reported.14 Of note, it is estimated that a genetic diagnosis can still not be made in 51-71% of all suspected cases, despite the introduction of whole exome sequencing. This is due to the large number of genes involved in HSP and the regular discovery of new genes.14 Gait functioning As illustrated above, the ability to walk is an important part of daily living: it enables us to move around within our home and community, and is, therefore, an important factor promoting independent living, social participation and quality of life.15,16 It requires more than just lifting one foot and placing it in front of the other. In contrast, purposeful walking requires a sufficient level of gait functioning that consists of three aspects: stepping, maintaining dynamic balance, and gait adaptability.17 Stepping First, people have to generate a basic stepping pattern. This relates to the rhythmic and repetitive movements of the legs in interaction with the trunk in order to generate propulsion (i.e., forward movement of the body).17 The description of the stepping pattern is commonly based on distance (i.e., spatial) or time (i.e., temporal) spanned between gait events, referred to as spatiotemporal gait parameters (e.g., step length, step width or step time). Furthermore, position and orientation of body segments is often used, referred to as joint kinematics (e.g., knee flexion or extension). Maintaining dynamic balance Second, people require dynamic balance control, referring to the ability to remain stable and upright while walking, despite the occurrence of both selfinitiated perturbations (e.g., the destabilizing impact of ankle push-off required for forward propulsion) and external perturbations (e.g., bumping into another person or walking over uneven terrain).17 To recover from such perturbations requires sufficient proactive and reactive balance control, depending on a wellfunctioning sensory system to adequately register when dynamic balance is jeopardized, and a good motor system to generate a coordinated response. Then, three strategies can be used to maintain balance while walking. Preferred are 1) the foot placement strategy (i.e., people alter foot placement of the swing leg to adjust 1
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