Pediatric <scp>Leigh</scp> Syndrome: Neuroimaging Features and Genetic Correlations

Stenton, Sarah L.; Zou, Youlan; Cheng, Hua; Prokisch, Holger; Fang, Fang

doi:10.1002/ana.25998

Cited by 4 publications

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“…Another interesting finding from this study is the association of caudate involvement with disease burden, progression, and mortality. The majority of patients in this study have striatal changes (putamen and caudate) within the basal ganglia, and this is similarly reported in the literature 29–31 . Often these basal ganglia structures were involved together, probably as a consequence of their close anatomical and physiological integration 32,33 .…”

Section: Discussionsupporting

confidence: 79%

“…The majority of patients in this study have striatal changes (putamen and caudate) within the basal ganglia, and this is similarly reported in the literature. 29 , 30 , 31 Often these basal ganglia structures were involved together, probably as a consequence of their close anatomical and physiological integration. 32 , 33 In a Ndufs4 knockout mouse model of Leigh syndrome and complex I deficiency, the selective inactivation of these striatal neurons led to progressive motor impairment.…”

Section: Discussionmentioning

confidence: 99%

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

Lim

Blain

et al. 2021

Annals of Neurology

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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.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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

Lim

Blain

et al. 2021

Annals of Neurology

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“…41 As required for the diagnosis of LS, all patients displayed characteristic bilateral lesions in the basal ganglia (77%) or brainstem (73%), or both (49%) on MRI and/or DWI, in addition to less frequently reported neuroradiological abnormalities, such as cerebral atrophy (34%), white matter involvement (19%), and cerebellar lesions (17%). In search of brain MRI features indicative of specific molecular genetic diagnoses, we found MT-ND5 to be depleted for basal ganglia lesions, and SURF1 to be associated with medulla oblongata lesions and cerebellar involvement, and depleted for basal ganglia lesions, associations we have previously described in a subset of 139 patients from our cohort 10 and partially supported in an independent cohort of 53 LS brain MRI datasets, 8 among other smaller studies. 38 Importantly, we found regression of MRI abnormalities to invariably result in a corresponding clinical improvement in the patient, and enrichment for progression of the MRI lesions in patients with clinical deterioration resulting in death, indicating radiological features to have the potential to serve as therapeutic biomarkers in future clinical trials.…”

Section: Discussionsupporting

confidence: 82%

“…7 Although all patients with these features are gathered under the clinical diagnosis of LS, irrespective of their underlying genetic diagnosis, there is increasing recognition of genetic defect-specific patterns of onset and survival, in addition to clinical, metabolic, and brain MRI features. [8][9][10] Defect-specific onset and survival data in LS, however, remains limited. 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.…”

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confidence: 99%

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

Stenton

Zou

Cheng

et al. 2022

Annals of Neurology

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Objective: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. Methods: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. Results: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176T>C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993T>C and m.9176T>C), SURF1, and ALDH5A1 (≤50% 3 year's survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year's survival). Interpretation: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counseling, and to the design and monitoring of future clinical trials, the next frontier of LS research.

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Leigh syndrome

Rahman¹

2023

Handbook of Clinical Neurology

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Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations

Cited by 4 publications

References 4 publications

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

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

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

Leigh syndrome

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