Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency

Leshinsky‐Silver, Esther; Levine, Arie; Nissenkorn, Andreea; Barash, V.; Perach, Michal; Buzhaker, E; Shahmurov, Mark; Polak-Charcon, S; Lev, Dorit; Lerman‐Sagie, Tally

doi:10.1016/s1096-7192(03)00097-0

Cited by 38 publications

(18 citation statements)

References 12 publications

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“…9,32 Prompt recognition of this subgroup of LS is imperative, because these patients may respond to CoQ 10 supplementation and survive into adulthood, 32 although this has not been consistently observed. 33 One report described improvement of hepatic but not neurological symptoms, 34 and another patient with CoQ 10 -deficient LS due to PDSS2 mutations did not respond to treatment. 9 …”

Section: Biochemical Deficiency Genesmentioning

confidence: 99%

Leigh syndrome: One disorder, more than 75 monogenic causes

Lake

Compton

Rahman

et al. 2015

Annals of Neurology

423

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: Biochemical Deficiency Genesmentioning

confidence: 99%

Leigh syndrome: One disorder, more than 75 monogenic causes

Lake

Compton

Rahman

et al. 2015

Annals of Neurology

423

382

View full text Add to dashboard Cite

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“…This hypothesis was supported by the restoration of complex II þ III activity after incubation with exogenous ubiquinone (decylubiquinone) (Supplementary Figure 1). 7,8 Unfortunately, we did not have enough material to perform a direct measurement of CoQ 10 content in the patient's liver. We analyzed microsatellite DNA markers flanking 17 genes known to be involved in CoQ 10 biosynthesis pathway and found homozygosity for the two affected children at the PDSS2 and ADCK4 loci.…”

Section: Rc Dysfunction In Fibroblasts and Livermentioning

confidence: 99%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

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“…This is an autosomal recessive disorder with a clinical spectrum that encompasses several main phenotypes [4]: a myopathic form, with myoglobinuria, epilepsy and ataxia [3,5]; a severe infantile syndrome with encephalopathy and renal disease [6]; and an ataxic form presenting with cerebellar atrophy [7]. However, other phenotypes have been reported, such as a neonatal presentation with fatal evolution [8], Leigh syndrome in adulthood [9], and liver failure plus Leigh syndrome [10]. A common feature in these cases is the presence of a variable degree of CoQ deficiency in muscle and/or fibroblasts causing decreased activities of NADH:cit c oxidoreductase and succinate:cit c oxidoreductase of the MRC.…”

Section: Introductionmentioning

confidence: 99%