Genetic and biochemical findings in Chinese children with Leigh syndrome

Ma, Yanyan; Wu, Tong-Fei; Liu, Yu-Peng; Wang, Qiao; Song, Jinqing; Li, Xiyuan; Shi, Xiaolan; Zhang, Weina; Zhao, Meng; Hu, Liang; Yang, Yanling; Zou, Li‐Ping

doi:10.1016/j.jocn.2013.03.034

Cited by 36 publications

(39 citation statements)

References 17 publications

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“…Isolated complex IV deficiency and multiple OXPHOS defects are also frequently observed, whereas defects of complexes II, III, or V or of CoQ 10 are relatively rare. 2,6,7 Measurement of OXPHOS and PDHc enzymes in a patient biopsy or cell line is often undertaken to provide evidence of a biochemical defect in these pathways to support a clinical diagnosis of LS.…”

Section: The Development Of Our Understanding Of the Etiological Basimentioning

confidence: 99%

“…2,6,7 Mutations in the NADH dehydrogenase (ubiquinone) Fe-sulfur protein 4 (NDUFS4) subunit are the most frequent autosomal recessive cause of complex I-associated LS, with > 20 cases reported. 24 Interestingly, almost all patients reported with NDUFS4 mutations had LS, in contrast to mutations in other nuclear-encoded complex I subunits, which may be associated with heterogeneous phenotypes.…”

Section: Complex I Deficiencymentioning

confidence: 99%

“…2,6,7,28 Mutations in the complex II subunit SDHA were the first nuclear mutations identified to cause OXPHOS disease. 29 Some patients with SDHA mutations have a severe infantile presentation of LS with rapid demise, 29 but other patients may experience a mild LS course, with survival into late childhood years, preservation of cognitive abilities, and an "almost normal …”

Section: Complex II Complex Iii and Coq 10 Deficienciesmentioning

confidence: 99%

“…2,6,7 Mutations in SURF1, encoding a complex IV assembly factor, are the most common cause of complex IV deficient LS and are among the most frequently reported causes of LS, with >200 cases described to date in the literature. 35 Our recent natural history study of a SURF1 patient cohort highlighted the relatively homogenous clinical and biochemical presentation associated with SURF1 deficiency.…”

Section: Complex IV Deficiencymentioning

confidence: 99%

“…Cohort studies have suggested that mtDNA mutations underlie approximately 10 to 20% of LS cases. 2,6,7 To date, mutations in 13 of the 37 mtDNA-encoded genes have been described to cause LS, with the majority in genes encoding subunits of complex I or V, or in mitochondrial tRNAs (see Table 1, and Supplementary Table, A for more detailed information). LS can also be caused by large-scale mtDNA deletions.…”

Section: -39mentioning

confidence: 99%

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Leigh syndrome: One disorder, more than 75 monogenic causes

Lake

Compton

Rahman

et al. 2015

Annals of Neurology

391

382

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Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options.

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Section: The Development Of Our Understanding Of the Etiological Basimentioning

confidence: 99%

Section: Complex I Deficiencymentioning

confidence: 99%

Section: Complex II Complex Iii and Coq 10 Deficienciesmentioning

confidence: 99%

Section: Complex IV Deficiencymentioning

confidence: 99%

Section: -39mentioning

confidence: 99%

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Leigh syndrome: One disorder, more than 75 monogenic causes

Lake

Compton

Rahman

et al. 2015

Annals of Neurology

391

382

View full text Add to dashboard Cite

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Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

Yang

Cao

Song

et al. 2022

American J of Med Genetics Pt A

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Leigh syndrome (LS), the most common mitochondrial disease in early childhood, usually manifests variable neurodegenerative symptoms and typical brain magnetic resonance imaging (MRI) lesions. To date, pathogenic variants in more than 80 genes have been identified. However, there are still many cases without molecular diagnoses, and thus more disease-causing variants need to be unveiled. Here, we presented three clinically suspected LS patients manifesting neurological symptoms including developmental delay, hypotonia, and epilepsy during the first year of age, along with symmetric brain lesions on MRI. We explored disease-associated variants in patients and their nonconsanguineous parents by whole-exome sequencing and subsequent Sanger sequencing verification. Sequencing data revealed three pairs of diseaseassociated compound heterozygous variants: c.1A>G (p.Met1?) and 409G>C (p. Asp137His) in SDHA, c.1253G>A (p.Arg418His) and 1300C>T (p.Leu434Phe) in NARS2, and c.5C>T (p.Ala2Val) and 773T>G (p.Leu258Trp) in ECHS1. Among them, the likely pathogenic variants c.409G>C (p.Asp137His) in SDHA, c.1300C>T (p. Leu434Phe) in NARS2, and c.773T>G (p.Leu258Trp) in ECHS1 were newly identified. Segregation analysis indicated the possible disease-causing nature of the novel variants. In silico prediction and three-dimensional protein modeling further suggested the potential pathogenicity of these variants. Our discovery of novel variants expands the gene variant spectrum of LS and provides novel evidence for genetic counseling.

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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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Genetic and biochemical findings in Chinese children with Leigh syndrome

Cited by 36 publications

References 17 publications

Leigh syndrome: One disorder, more than 75 monogenic causes

Leigh syndrome: One disorder, more than 75 monogenic causes

Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

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

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