Elsevier

Gait & Posture

Volume 36, Issue 3, July 2012, Pages 619-624
Gait & Posture

Balance impairment in individuals with Wolfram syndrome

https://doi.org/10.1016/j.gaitpost.2012.06.008Get rights and content

Abstract

Aim

Wolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test.

Method

Balance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals.

Results

A significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age.

Interpretation

Impairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms.

Highlights

► Identifies, previously unreported, early neurological complications in Wolfram syndrome (WFS). ► Individuals with WFS present with impaired balance. ► Supports the MiniBESTest as a clinical measure of balance impairment.

Introduction

Wolfram syndrome (WFS) is an early onset, autosomal recessive, neurodegenerative disorder with a reported prevalence between 1 in 100,000 [1] and 1 in 770,000 [2]. Typically, the first diagnosed symptom of WFS is diabetes mellitus (median age at diagnosis = 6 years) followed by optic atrophy (median age of diagnosis between 9 and 13 years) [3], [4], [5], [6], [7]. The combination of these two manifestations was originally described in four siblings by Wolfram and Wagener in 1938 [8] and is still considered to be the primary feature set of WFS. Since the original report, renal tract abnormalities, deafness, diabetes insipidus, gonadal disorders, and a range of psychological and neurological complications have also been frequently reported (for review see [9] and [10]). Affected individuals have a median life expectancy of 30 years, with early mortality credited to neurological disorders, urological abnormalities and infection [4].

There is currently no cure for WFS. Differential diagnosis and treatment are difficult due to the variable presentation of symptoms [9]. Genetic testing for the WFS1 gene is available once WFS is suspected, but no current therapeutic genetic intervention is available. Therefore, identifying the symptoms that can be addressed via patient-centered treatment paradigms is vital for maintaining the highest possible quality of life for individuals with WFS.

Due to the underlying neurologic condition, maintaining functional motor performance or delaying motor decline should be a primary focus of clinical intervention for individuals with WFS. To date, neurological complications related to motor function have been incompletely studied in the WFS population. Ataxia is the most commonly reported motor manifestation [2], [7], [11], but has not been quantitatively evaluated. Additionally, evidence from MRI studies suggests the presence of severe atrophy in the cerebellum and brainstem of some individuals with WFS [7], [12], [13]. As the cerebellum [14], [15], [16] and brainstem [17] play important roles in balance, we suggest it would be essential to assess balance in individuals with WFS.

The purpose of this study was to determine if balance is impaired in young individuals with WFS as compared to typically developing, age-matched controls. We hypothesized that quantifiable deficits in balance may be present in the WFS population as compared to typically developing, age-matched individuals and that these deficits may be present much earlier in life than previously reported [2], [7]. Furthermore, we sought to measure balance in a manner that is both time-sensitive and clinically relevant, but still provides insight into the nature of the deficit.

A clear determination and quantification of an easily tested metric could offer insight into disease progression, offer additional diagnostic support, and help to focus rehabilitative methods for those individuals currently affected by this disease.

Section snippets

Participants

Thirteen individuals diagnosed with Wolfram syndrome (8 female, mean age 15.5 ± 6.3 years, min 6.4 years, max 25.8 years) and 29 neurologically healthy young individuals (16 female, mean age 13.4 ± 6.1 years, min 5.6 years, max 28.46 years) completed all phases of the experiment. One typically developing individual (age 5.6 years) attempted to participate but was removed from data analysis as he was not able to complete all tasks independently. Participants were recruited via the Washington

Clinical assessment

Demographic data for both groups are shown in Table 1. WFS and age-matched controls did not differ by age (z = 1.08, p = 0.28), height (z = −0.59, p = 0.56), weight (z = 0.37, p = 0.71), or year in school (z = 1.06, p = 0.29). A significant difference was present between groups for the raw score on the Gross Motor subsection score of the PANESS, with the WFS group showing a significantly greater level of motor impairment (z = 3.72, p  0.001).

Balance assessment

Total mini-BESTest scores were higher (less impaired) for the typically

Discussion

The primary aim of this study was to determine if balance is impaired in early WFS as compared to typically developing age-matched controls. Our findings indicate not only an overall difference in balance between individuals with WFS and typically developing age-matched individuals, but more specifically deficits in the anticipatory transitions, postural responses and sensory orientation subcomponents. Dynamic gait was not significantly impacted in the WFS group.

In this investigation, the

Conclusions

These findings suggest that individuals with WFS present with balance deficits compared to age-matched controls, when assessed with a quantitative, objective clinical tool (mini-BESTest). These impairments were evident earlier in the disease progression than previously recognized through clinical retrospective studies. Thus, clinicians with younger WFS patients should examine balance and design patient-centered treatment paradigms to address the needs of these individuals to maximize quality of

Funding

This work was supported by Jack and J.T. Snow Fund at Washington University, the George Decker and Julio V. Santiago Pediatric Diabetes Research Fund, and the National Institutes of Health [grant numbers DK016746-39, NCRR 1S10RR022984-01A1 and UL1 RR024992 to Washington University. Individual authors Paciorkowski and Pickett are support by T32 NS051171-04 and 2T32 HD007434-18, respectively.

Acknowledgements

The authors thank the participants and their families for their time and willingness to participate.
Conflicts of interest statement

The authors declare that they have no conflicts of interest and all funding sources have been disclosed above.

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