Abstract
ObjectiveThis observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome.MethodsSeventy‐two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at baseline at 3.7 years (interquartile range [IQR] = 2.0–7.6) and follow‐up assessments at 7.5 years (IQR = 3.7–11.0) in clinics were enrolled. Eighty‐two percent of this cohort had a confirmed genetic diagnosis, with pathogenic variants in the MT‐ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0–14), moderate (15–25), and severe (>25) disease burden. Detailed clinical, neuroradiological, and molecular genetic findings were also analyzed.ResultsThe median total NPMDS scores rose significantly (Z = −6.9, p < 0.001), and the percentage of children with severe disease burden doubled (22% → 42%) over 2.6 years of follow‐up. Poor function (especially mobility, self‐care, communication, feeding, and education) and extrapyramidal features contributed significantly to the disease burden (τ b ≈ 0.45–0.68, p < 0.001). These children also deteriorated to wheelchair dependence (31% → 57%), exclusive enteral feeding (22% → 46%), and one‐to‐one assistance for self‐care (25% → 43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow‐up NPMDS scores (disease burden; p < 0.001) and steeper increase in NPMDS score per annum (disease progression; p < 0.001). Other predictors of poor outcomes include SURF1 gene variants (p < 0.001) and bilateral caudate changes on neuroimaging (p < 0.01).InterpretationThis study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. ANN NEUROL 2022;91:117–130
Highlights
This study aims to identify factors that may determine disease trajectory and begins to address the void in systematic, purposeful natural history data collection
All patients recruited to the study fulfilled the diagnostic criteria for Leigh syndrome[9]: (1) intellectual and motor developmental delay and/or regression; (2) clinical manifestation of corresponding symmetrical brainstem and/or basal ganglia neuroradiological changes; and (3) abnormal metabolism characterized by a defect in oxidative phosphorylation or pyruvate dehydrogenase complex activity, a molecular genetic diagnosis related to mitochondrial dysfunction, or elevated lactate in cerebrospinal fluid (CSF; >1.8mmol/l) or blood samples (>2.2mmol/l)
Repeated use of the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at multiple outpatient clinic attendances provides quantitative data on the disease severity of Leigh syndrome and allows disease trajectories to be plotted for individual patients
Summary
This observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome. We sought to quantify the disease burden and rate of progression of Leigh syndrome using a validated and established clinical scale, the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS).[10] This study aims to identify factors that may determine disease trajectory and begins to address the void in systematic, purposeful natural history data collection. Data from this and subsequent studies will be crucial to the successful design of future clinical trials in mitochondrial disease
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