Abstract
BackgroundMyelopathy is the core clinical manifestation of adrenoleukodystrophy (ALD), which is the most common peroxisomal disorder. Development of therapies requires sensitive and clinically relevant outcome measures. Together with spastic paraparesis, balance disturbance is the main cause of disability from myelopathy in ALD. In this cross-sectional study, we evaluated whether postural body sway – a measure of balance – could serve as a surrogate outcome in clinical trials.MethodsForty-eight male ALD patients and 49 age-matched healthy male controls were included in this study. We compared sway amplitude and sway path of ALD patients to controls. We then correlated the body sway parameters showing the largest between-group differences with clinical measures of severity of myelopathy. To correct for age, we performed multiple linear regression analysis with age and severity of myelopathy as independent variables.ResultsAll body sway parameters were significantly higher in patients than in controls, with medium to large effect sizes (r = 0.43–0.66, p < 0.001). In the subgroup of asymptomatic patients, body sway amplitude was also higher, but the difference with controls was smaller than for symptomatic patients (effect size r = 0.38–0.46). We found moderate to strong correlations between body sway amplitude and clinical severity of myelopathy (r = 0.40–0.79, p < 0.005). After correction for age, severity of myelopathy was a significant predictor of body sway amplitude in all regression models.ConclusionsThese results indicate that postural body sway may serve as a surrogate outcome for myelopathy in ALD. Such outcomes are important to evaluate new therapies in clinical trials. Further longitudinal studies are needed and ongoing in this cohort.
Highlights
Progressive myelopathy affects almost all men with X-linked adrenoleukodystrophy (ALD) (Moser et al, 2001; Huffnagel et al, 2019b)
For the patients included in this particular study, 32/48 (67%) were symptomatic, meaning that they had both signs and symptoms of myelopathy
The median score on the Expanded Disability Status Scale (EDSS) was 3.5 (IQR 0.25– 6.0) and that on the system for Progressive Myelopathy (SSPROM) 87.3 (IQR 76.4–100), and the mean distance walked on 6-minute walk test (6MWT) was 509.0 (SD 176.7) m
Summary
Progressive myelopathy affects almost all men with X-linked adrenoleukodystrophy (ALD) (Moser et al, 2001; Huffnagel et al, 2019b). ALD is a genetic neurometabolic disorder with an estimated incidence of 1 in 17000 (Bezman et al, 2001) It is caused by mutations in the ABCD1 gene that encodes the peroxisomal transmembrane transporter (referred to as ABCD1 protein) for very long-chain fatty acids (VLCFA) (Mosser et al, 1993; van Roermund et al, 2008). Symptoms of myelopathy typically start in the 3rd to 4th decades with a slowly progressive gait disorder (Engelen et al, 2012) Sphincter disturbance with both urinary and fecal incontinence is frequently reported. Balance disturbance is the main cause of disability from myelopathy in ALD In this cross-sectional study, we evaluated whether postural body sway – a measure of balance – could serve as a surrogate outcome in clinical trials
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