Early presentation of gait impairment in Wolfram Syndrome

Abstract

Background: Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease.

Methods: Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups.

Results: Across all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs = 0.564, p = 0.045) and dual task forward walking (rs = 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = -0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = -0.64, p = 0.03).

Conclusions: Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS.

Figure 1

Tandem gait trials were assessed by counting the number of times the individual had a footfall or series of footfalls off the linear path of progression. (A) Trials in which all steps fell on the linear trajectory were scored as no missteps. Trials with one (B) or multiple (C) missteps were scored on the number of times the individual deviated from the linear trajectory and not on the number of individual steps that were off that trajectory.

Figure 2

Cadence (A), normalized velocity (B), average normalized base of support (C), average step extremity ratio (D) and percentage of gait cycle spent in double support (E) of individuals with WFS (black bars) and TD individuals (gray bars) during forward preferred, forward fast, dual task and backward walking tasks. Cadence values did not differ between groups. Group level differences were present for all other spatiotemporal measures. Values are mean +/− SD.

Figure 3

Cadence versus age for individuals with WFS (black) and TD individuals (gray) during (A) forward preferred, (B) forward fast, (C) dual task and (C) backward walking tasks. Cadence was significantly correlated with age in all four task conditions for the TD individuals. Cadence was not significantly correlated with age for individuals with WFS in any condition.

Figure 4

Significant correlations between mini-BESTest and (A) normalized velocity during forward fast gait and (B) percentage of the gait cycle spent in double support for the WFS group. Higher mini-BESTest scores correspond to better balance.