Specific Gait Changes in Prodromal Hereditary Spastic Paraplegia Type 4: preSPG4 Study

Abstract

Background In hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested. Objective The objective of this study was to identify specific movement abnormalities before the manifestation of gait impairment and quantify disease progression in the prodromal phase. Methods Seventy subjects participated in gait assessment, including 30 prodromal SPAST pathogenic variant carriers, 17 patients with mild‐to‐moderate manifest SPG4, and 23 healthy control subjects. An infrared‐camera‐based motion capture system assessed gait to analyze features such as range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale, neurofilament light chain as a fluid biomarker indicating neurodegeneration, and motor‐evoked potentials. Results Compared with healthy control subjects, we found an altered gait pattern in prodromal pathogenic variant carriers during the swing phase in the segmental angle of the foot (Dunn's post hoc test, q = 3.1) and heel ground clearance (q = 2.8). Furthermore, range of motion of segmental angle was reduced for the foot (q = 3.3). These changes occurred in prodromal pathogenic variant carriers without quantified leg spasticity in clinical examination. Gait features correlated with neurofilament light chain levels, central motor conduction times of motor‐evoked potentials, and Spastic Paraplegia Rating Scale score. Conclusions Gait analysis can quantify changes in prodromal and mild‐to‐moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Dysfunctional neuro-muscular mechanisms explain gradual gait changes in prodromal spastic paraplegia

“…On the kinematic level, the earliest gait changes in prodromal SPG4 subjects occur in the foot segment and ankle joint (Lassmann et al, 2022). Increasing muscle spindle velocity feedback (𝜔 ℎ ) in the simulation caused several gait changes that are in line with kinematic changes of heel strike walking in prodromal subjects and early-to-moderate manifest SPG4 patients.…”

“…This thought experiment indicates that pharmacological reduction of spasticity in early SPG4 patients could delay the onset of manifest spastic gait. In the currently running longitudinal experimental study (Rattay et al, 2022;Lassmann et al, 2022) Further studies are needed to objectively measure altered sensory-motor reflex loops and axonal damage in prodromal and early-to-moderate SPG4 subjects, e.g., a dynamometer-based H-reflex measure and corticomuscular coherence measure, respectively.…”

“…The planar model was used, since the most prominent differences between healthy controls, prodromal SPG4, and manifest SPG4 patients were found in the flexion and extension angles especially in the foot segment (Lassmann et al, 2022). We modeled seven Hill-type muscles (Millard-equilibrium muscle model (Millard et al, 2013)), namely Gluteus maximus (GLU), Iliopsoas (IL), Rectus femoris (RECT), Vastus intermedius (VAS), Gastrocnemius medialis (GAS), Soleus (SOL), and Tibilias anterior (TA) per leg.…”

“…We have recently shown for hereditary spastic paraplegia type 4 (SPG4) subjects -the most common autosomal dominant and pure motor form of HSP (Rattay et al, 2022;Hazan et al, 1999) -that specific subtle changes in the kinematic gait pattern can be detected by quantitative movement analysis in the prodromal phase, before the manifestation of spastic gait (Lassmann et al, 2022). Changes that can be observed early are increased minimum plantarflexion or reduced foot range of motion (RoM) which gradually increase in early manifest stages (Lassmann et al, 2022), leading to gait patterns affecting the ankle, knee, and hip joints (Martino et al, 2018(Martino et al, , 2019Piccinini et al, 2011). Especially the foot RoM and minimum plantarflexion show significant correlations to disease severity already in prodromal and early manifest stages (Lassmann et al, 2022).…”

“…The origin of these pathologies is a length-dependent affection of the cortico-spinal tract (Harding, 1983;Fink, 2006). Due to the length-dependency, early gait changes have been primarily observed in the ankle joint (Lassmann et al, 2022;Serrao et al, 2016). Brisk patellar and Achilles reflexes can be observed in clinical examinations already in the prodromol phase (Rattay et al, 2022).…”