Abstract
Mitochondrial disease is complex and variable, making diagnosis and management challenging. The situation is complicated by lack of sensitive outcomes of disease severity, progression, contributing pathology and clinical efficacy. Gait is emerging as a sensitive marker of pathology; however, to date, no studies have quantified gait in mitochondrial disease. In this cross-sectional study, we quantified gait characteristics in 24 patients with genetically confirmed mitochondrial disease (m.3243A>G and m.8344A>G) and 24 controls. Gait was measured using an instrumented walkway according to a predefined model with five domains hypothesised to reflect independent features of the neural control of gait in mitochondrial disease, including: pace (step velocity and step length); rhythm (step time); variability (step length and step time variability); asymmetry (step time asymmetry); and postural stability (step width, step width variability and step length asymmetry). Gait characteristics were compared with respect to controls and genotype. Additional measures of disease severity, pathophysiology and imaging were also compared to gait to verify the validity of gait characteristics. Discrete gait characteristics differed between controls and mitochondrial disease groups, even in relatively mildly affected patients harbouring the m.3243A>G mutation. The pattern of gait impairment (increased variability and reduced postural control) was supported by significant associations with measures of disease severity, progression, pathophysiology and radiological evidence of cerebellar atrophy. Discrete gait characteristics may help describe functional deficits in mitochondrial disease, enhance measures of disease severity and pathology, and could be used to document treatment effects of novel therapies.
Highlights
Mitochondrial disorders are one of the commonest inherited neuromuscular disorders and present with a highly variable and complex pattern of neurological and systemic involvement [1]
We used a robust model to capture the complexity of gait, which enabled us to differentiate mitochondrial genotypes and identify the pattern of gait deficits potentially reflecting differences in the underlying pathophysiology and neural control of locomotion
Gait impairment was observed in both the mitochondrial disease group and individual genotypes compared to controls
Summary
Mitochondrial disorders are one of the commonest inherited neuromuscular disorders and present with a highly variable and complex pattern of neurological and systemic involvement [1]. Whilst progress has been made identifying definitive genotypes in mitochondrial diseases, this is of limited help to the clinician or patient because of considerable heterogeneity in phenotype, which can be only partly explained by the level of mutant and wild type mtDNA present (heteroplasmy). Phenotypic heterogeneity is reflected by the highly variable presentation of clinical features [2]. The relationship between clinical outcomes, genotype and heteroplasmy is complex and. J Neurol (2014) 261:73–82 current clinical outcomes do not accurately discriminate for genotype or heteroplasmy, thereby limiting understanding of disease evolvement, underlying pathology and appropriate interventions. Gait is emerging as a powerful measurement tool to identify markers of incipient pathology, inform diagnostic algorithms and disease progression, and measure efficacy of interventions [4]. To date no studies have carried out a detailed quantification of gait in patients with mitochondrial disease
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