By Eric Mallack, MD
Assistant Professor of Pediatrics and Neurology, Division of Child Neurology, Weill Cornell Medical College; Director, Leukodystrophy Center at Weill Cornell Medicine
SYNOPSIS: The natural history of Leigh syndrome is characterized by quantifiable disease progression in fewer than three years, with the poorest outcomes predicted by surfeit locus protein 1 (SURF1) pathogenic variants, bilateral caudate involvement on magnetic resonance imaging, and rapid increases in yearly Newcastle Paediatric Mitochondrial Disease Scale scores.
SOURCE: Lim AZ, Ng YS, Blain A, et al. Natural history of Leigh syndrome: A study of disease burden and progression. Ann Neurol 2022;91:117-130.
Leigh syndrome predominantly is a childhood-onset progressive neurodegenerative disorder. It is caused by pathogenic variants in nuclear and mitochondrial genes that encode proteins required for oxidative phosphorylation and pyruvate dehydrogenase activity.
Abnormal mitochondrial metabolism in the central nervous system leads to a subacute necrotizing encephalomyelopathy most often affecting the basal ganglia and brainstem. Although the syndrome is well characterized, little is known about the rate of disease progression. The investigators quantified the rate of disease progression using the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at two timepoints in 72 children, median age 3.7 years, over a median time of 2.6 years.
Clinically, extrapyramidal symptoms correlated most strongly with mobility and total NPMDS scores. Functionality, communication, education, feeding, and self-care all are interrelated, and all correlated with the total NPMDS scores. The median survival was 4.0 years of age, with a mean of 7.3 years of age. Twelve patients were deceased by the end of the study. Patients in the deceased group had the highest follow-up NPMDS scores in feeding, respiration, and pyramidal assessments.
Notable accelerants to disease progression included patients who harbored pathogenic surfeit locus protein 1 (SURF1) variants, and patients with disease onset before the age of 6 months, bilateral caudate involvement, and generalized atrophy. Worse overall survival was associated with bilateral cerebellar and bilateral caudate involvement, baseline severe NPMDS scores, and those with an NPMDS change > 3 per annum.
COMMENTARY
Sound, well-executed, longitudinal natural history studies in the rare disorders are, in fact, rare. They are required to understand disease progression, clinical management, and prognostication. Moreover, in the era of novel genetic therapies for rare neurogenetic diseases — viral-mediated gene therapy, antisense oligonucleotide therapy, and CRISPR gene editing — natural history studies are necessary to serve as the control group to assess efficacy of novel therapies by clinical trial.1-5 The work by Lim et al represents substantial progress in understanding the natural history of Leigh syndrome.
In addition to identifying negative prognostic indicators, the characterization and change in disease burden provide a landscape view of how children are affected by disease over time despite the genetic heterogeneity characteristic to this syndrome. However, as noted by the authors, this study has two main limitations. The study group likely has been biased by survivorship: Patients with the most severe disease early in life who underwent very rapid deterioration were not included.
The second limitation is the ceiling effect of the NPMDS, which may underestimate the true burden of disease in the most affected patients. Overall, this work represents the foundation by which the field may develop and measure future therapeutic approaches for this devastating group of disorders.
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