Management of Leigh syndrome: Current status and new insights

Chen, Ling; Cui, Yu; Jiang, Dan; Yan, Chui; Tse, Hung‐Fat; Hwu, Wuh‐Liang; Lian, Qizhou

doi:10.1111/cge.13139

Cited by 22 publications

(45 citation statements)

References 93 publications

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“…LS is clinically recognized as an early‐onset, fatal neurodegenerative disorder with few specific treatment options. No curative treatments aside from supportive care and a multivitamin cocktail have been available, although some in vitro and in vivo studies on Ndufs4 knockout mouse models and clinical trials for novel treatments have been conducted . Recently, a high‐dose thiamine‐biotin combination treatment for LS patients with SLC19A3 mutations was shown to afford clinical improvement and prevent neurologic dysfunction .…”

Section: Discussionmentioning

confidence: 99%

“…Our advanced, deep bioinformatic analysis overcame some limitations in capture and coverage of WES, leading to a high diagnostic yield rate. Uncovering molecular defects can help us understand the complex pathogenesis of LS, paving the way for development of curative treatment options and potential therapeutic strategies, including stem cell‐derived mitochondrial donation or CRISPR/Cas9 genome editing . In genetically unsolved cases, RNA sequencing of muscle biopsy or induced pluripotent stem cells might be needed.…”

Section: Discussionmentioning

confidence: 99%

“…No curative treatments aside from supportive care and a multivitamin cocktail have been available, although some in vitro and in vivo studies on Ndufs4 knockout mouse models and clinical trials for novel treatments have been conducted. 6,7,9 Recently, a high-dose thiamine-biotin combination treatment for LS patients with SLC19A3 mutations was shown to afford clinical improvement and prevent neurologic dysfunction. 22,23 SLC19A3 encodes the thiamine transporter hTHTR2, and its defects result in thiamine deficiency, which leads to pyruvate dehydrogenase deficiency and ultimately to brain mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Whole‐exome sequencing (WES) of the nDNA has revealed well‐known common causes, such as genes encoding oxidative phosphorylation (OXPHOS) subunits or assembly factors, and genetic defects associated with functional maintenance or translation of mitochondria and with secondary impairment of mitochondrial energy generation . Recent reports have also shown that early diagnosis and management of some treatable cases of LS can prevent neurologic deterioration and improve quality of life …”

Section: Introductionmentioning

confidence: 99%

“…5,6 Recent reports have also shown that early diagnosis and management of some treatable cases of LS can prevent neurologic deterioration and improve quality of life. 6,7 In this study, we analyzed the molecular defects of LS, including novel genetic causes, and evaluated the associations between genotype and phenotype to help explain the pathogenesis of LS.…”

mentioning

confidence: 99%

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Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole‐exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin‐thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

et al. 2020

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Phenotypic variability and mutation hotspot in COX15‐related Leigh syndrome

Halpérin

Drabkin

Wormser

et al. 2020

American J of Med Genetics Pt A

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COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain.Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole-exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation.We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.

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Metabolic rescue ameliorates mitochondrial encephalo‐cardiomyopathy in murine and human iPSC models of Leigh syndrome

Yoon

Daneshgar

Chu

et al. 2022

Clinical & Translational Med

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Background Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio‐encephalomyopathy in LS remains incompletely understood. Methods We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells‐derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency. Results LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human‐induced pluripotent stem cell‐derived cardiomyocytes (iPS‐CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD + /NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel Na V 1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD + ‐dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD + / NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD + ‐dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of Na V 1.5 current and SERCA2a function measured by Ca2 + ‐transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS‐derived neurons with Ndufs4 deletion. Conclusions Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS.

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Management of Leigh syndrome: Current status and new insights

Cited by 22 publications

References 93 publications

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Phenotypic variability and mutation hotspot in COX15‐related Leigh syndrome

Metabolic rescue ameliorates mitochondrial encephalo‐cardiomyopathy in murine and human iPSC models of Leigh syndrome

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