Mitochondrial disease in children

Rahman, Shamima

doi:10.1111/joim.13054

Cited by 85 publications

(72 citation statements)

References 164 publications

(203 reference statements)

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“…Besides being the direct cause of primary mitochondrial diseases, typically characterised by severe mitochondrial impairment in multiple tissues (Tuppen et al, 2010), mtDNA mutations have also been implicated in the pathophysiology of common age-associated human diseases (Reeve et al, 2008;Tuppen et al, 2010;Greaves et al, 2012;La Morgia et al, 2020;Rahman, 2020) and in the naturally occurring ageing process (Larsson, 2010). It is well established that point mutations in tRNA genes or single large deletions of mtDNA lead to functional impairment or lack of one or several tRNAs.…”

Section: Accepted Articlementioning

confidence: 99%

“…These disorders can affect different cell types and organs, and can therefore, cause a wide range of symptoms. Mitochondrial diseases have been classified according to their clinical manifestations and can be caused either by mutations in nuclear genes, leading to reduced mtDNA expression, or by primary mtDNA mutations directly impairing the function or abundance of mtDNA-encoded gene products (Rahman, 2020;La Morgia et al, 2020). mtDNA depletion syndromes (MDS) (Viscomi & Zeviani, 2017) are autosomal recessive disorders characterized by a strong tissue-specific reduction of mtDNA levels due to mutations in genes involved in various mtDNA maintenance processes, ranging from mitochondrial nucleotide metabolism, mtDNA replication, mitochondrial dynamics and quality control (Table 1).…”

Section: Mtdna Copy Number In Mitochondrial Diseasesmentioning

confidence: 99%

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Mitochondrial DNA copy number in human disease: the more the better?

et al. 2020

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Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene-dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.

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Section: Accepted Articlementioning

confidence: 99%

Section: Mtdna Copy Number In Mitochondrial Diseasesmentioning

confidence: 99%

Mitochondrial DNA copy number in human disease: the more the better?

et al. 2020

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“…Although mutations in mitochondrial disease genes are individually rare, mitochondrial disorders represent the largest group of inborn errors of metabolism, with a collective lifetime risk of 1.6 in 5,000 (Ferreira et al, 2019;Tan et al, 2020). To date, pathogenic variants in more than 400 genes, of both mitochondrial and nuclear origin, have been ascribed as causes of mitochondriopathies (Frazier et al, 2019;Falk, 2020;Rahman, 2020;Stenton and Prokisch, 2020).…”

Section: Mitochondrial Disordersmentioning

confidence: 99%

“…The number of nuclear genes associated with mitochondrial function is estimated to be ∼1500 (Calvo et al, 2016). So far, 376 of these genes have been associated with human mitochondrial disorders in total and as the routine use of NGS technologies grows, this number is expected to continuously increase (Frazier et al, 2019;Falk, 2020;Rahman, 2020;Stenton and Prokisch, 2020). Due to the capacity to detect pathogenic variants in genes so far not linked to mitochondrial disorders, the criteria for which genes should be classified as associated with a mitochondriopathy are now the subject to discussion.…”

Section: Definition Of Mitochondrial Disease Genesmentioning

confidence: 99%

The Dimensions of Primary Mitochondrial Disorders

Schlieben

Prokisch

2020

Front. Cell Dev. Biol.

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The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

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“…The very complex clinical presentations in children with mitochondrial diseases are summarized by Shamima Rahman [6]. In children, mitochondrial dysfunction typically causes multisystemic involvement and almost any organ can be affected.…”

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confidence: 99%