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

Albert Z Lim; Yi Shiau Ng; Alasdair Blain; Cecilia Jiminez-Moreno; Charlotte L Alston; Victoria Nesbitt; Louise Simmons; Saikat Santra; Evangeline Wassmer; Emma L Blakely; Doug M Turnbull; Robert W Taylor; Gráinne S Gorman; Robert McFarland

doi:10.1002/ana.26260

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

Ann Neurol. 2022 Jan;91(1):117-130. doi: 10.1002/ana.26260. Epub 2021 Nov 12.

Authors

Albert Z Lim^{1

2}, Yi Shiau Ng^{1

2}, Alasdair Blain¹, Cecilia Jiminez-Moreno¹, Charlotte L Alston^{1

2}, Victoria Nesbitt³, Louise Simmons⁴, Saikat Santra⁴, Evangeline Wassmer⁴, Emma L Blakely^{1

2}, Doug M Turnbull^{1

2}, Robert W Taylor^{1

2}, Gráinne S Gorman^{1

2}, Robert McFarland^{1

2}

Affiliations

¹ Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
² National Health Service Highly Specialised Services for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK.
³ National Health Service Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK.
⁴ Birmingham Children's Hospital, Birmingham, UK.

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 = -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).

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. ANN NEUROL 2022;91:117-130.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Child
Child, Preschool
Cohort Studies
Cost of Illness
Disease Progression
Female
Humans
Infant
Leigh Disease*
Longitudinal Studies
Male

Abstract

Publication types

MeSH terms

Grants and funding