Natural History of Leigh Syndrome: A Study of Disease Burden and Progression

Abstract

Objective: 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. Methods: Seventy-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. Results: The median total NPMDS scores rose significantly (Z = À6.9, 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). Interpretation: This 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.

Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

“…4 Elevated serum lactate is a readily measurable indicator in clinical practice. However, like previously described cohorts with reportedly normal serum/CSF lactate in 25 to 30% of cases, 11,13,29 in the investigated patients in our LS cohort, 26% of them had a normal serum lactate, and when measured on more than one visit in the same patient, discrepancies arose in almost 20%. This underlines the difficulty to appropriately interpret serum lactate, given the risk of missing a transient elevation in LS, and reporting a nonspecific elevation in an acutely unwell child, a struggling child, or due to firm tourniquet use.…”

“…The nuclear diagnoses stratify into 104 recessively inherited defects (89 compound heterozygous and 15 homozygous) and 18 XLD defects, of which 7 of 18 arose de novo (PDHA1 n = 6 and HSD17B10 n = 1). Across both genomes, most frequently, diseasecausing variant were identified in MT-ATP6 (n = 28) and SURF1 (n = 22), in keeping with other large LS cohorts reported in the literature 9,[11][12][13][14] (see Fig 1B,C).…”

“…14 We, however, report a 3 year survival of just 44% and found SURF1 to be among the most unfavorable defects. This finding is supported by the most recent LS cohort studies by Ardissone et al 11 and Lim et al, 13 reporting SURF1 to be the most severe defect across patients with LS in the Italian Collaborative Network of Mitochondrial Diseases and the Mitochondrial Disease Patient Cohort (MitoCohort) UK, respectively. One potential explanation for the discrepancy in SURF1 survival across cohorts is the near absence of overlap in the reported underlying variants, with just 3 of over 100 unique SURF1 variants found in common between our cohort and the Wedatilake et al 42 pooled study.…”

“…14,28,29 We report 42% of LS to be maternally inherited, this figure is in keeping with other large European and East Asian cohorts of patients with LS published in the last 5 years, collectively describing 514 genetically confirmed patients with LS, and reporting figures ranging from 27 to 52%. 9,[11][12][13][14] On the individual gene-level, combining these cohorts, MT-ATP6 accounts for the largest proportion of LS cases (18%) followed by SURF1 (15%), with all other defects accounting for <10% (see Fig 1B). The variable distribution of defects across East Asian and European cohorts suggests that genetic defects may vary based on ethnicity or between populations, such as due to founder mutations as previously described for ECHS1 and GTPBP3 in Chinese patients.…”

“…This limitation arises due to the rarity and broad genetic underpinning of the disease, with individual LS cohorts to date reaching approximately 100 genetically confirmed patients from European and East Asian populations. 9,[11][12][13][14] Here, we pave the way to overcome this shortfall by the characterization of 209 genetically confirmed patients with LS at the Beijing Children's Hospital, a national center specialized in the diagnosis of pediatric mitochondrial disease. We thereby resolve the clinical and genetic spectrum of the largest cohort of systematically evaluated patients with LS to date and uncover associations between genotype, phenotype, disease onset, and survival, essential in the design of future clinical trials for LS 15 by determining the most frequent genetic etiologies of LS and by enabling defect-specific definition of therapeutic effect on survival.…”