Mitochondrial leukoencephalopathies: A border zone between acquired and inherited white matter disorders in children?

Bindu, Parayil Sankaran; Kothari, Shawn; Chiplunkar, Shwetha; Govindaraj, Periyasamy; Nagappa, Madhu; Vekhande, Chetan Chandrakanth; Aravinda, Hanumanthapura R.; Ponmalar, JN Jessiena; Mahadevan, Anita; Gayathri, Narayanappa; Bharath, MM Srinivas; Sinha, Sanjib; Taly, Arun B.

doi:10.1016/j.msard.2018.01.003

Cited by 34 publications

(43 citation statements)

References 29 publications

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“…Both men had lived into their thirties when the study was conducted. A six-year-old boy was also found to carry the p.Gly32Arg mutation [45]. Though the age of onset was not recorded, he experienced episodic neuroregression and encephalopathy but was seizure-free.…”

Section: Ndufa1mentioning

confidence: 99%

Analysis of Human Mutations in the Supernumerary Subunits of Complex I

Dang

Phan

Johnson

et al. 2020

Life

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Complex I is the largest member of the electron transport chain in human mitochondria. It comprises 45 subunits and requires at least 15 assembly factors. The subunits can be divided into 14 “core” subunits that carry out oxidation–reduction reactions and proton translocation, as well as 31 additional supernumerary (or accessory) subunits whose functions are less well known. Diminished levels of complex I activity are seen in many mitochondrial disease states. This review seeks to tabulate mutations in the supernumerary subunits of humans that appear to cause disease. Mutations in 20 of the supernumerary subunits have been identified. The mutations were analyzed in light of the tertiary and quaternary structure of human complex I (PDB id = 5xtd). Mutations were found that might disrupt the folding of that subunit or that would weaken binding to another subunit. In some cases, it appeared that no protein was made or, at least, could not be detected. A very common outcome is the lack of assembly of complex I when supernumerary subunits are mutated or missing. We suggest that poor assembly is the result of disrupting the large network of subunit interactions that the supernumerary subunits typically engage in.

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Section: Ndufa1mentioning

confidence: 99%

Analysis of Human Mutations in the Supernumerary Subunits of Complex I

Dang

Phan

Johnson

et al. 2020

Life

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“…Typical Leigh syndrome [88,107] and late-onset Leigh syndrome have been reported [95,103] . The clinical course was variable with some patients having slower progression of neurological manifestations [90,91,103] . Brain MRI and MRS findings included features of typical Leigh syndrome, white matter changes, basal ganglia changes, elevated lactate peak, infantile striatal necrosis [97] , and cavitating leukoencephalopathy [109] .…”

Section: Fdxr Deficiency (Omim #617717)mentioning

confidence: 99%

Riboflavin metabolism: role in mitochondrial function

Balasubramaniam¹,

Yaplito‐Lee²

2020

jtgg

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Riboflavin, known as vitamin B2, a water-soluble vitamin, is an essential nutrient in vertebrates, hence adequate dietary intake is imperative. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. These flavocoenzymes ensure the functionality of numerous flavoproteins including dehydrogenases, oxidases, monooxygenases, and reductases, which play pivotal roles in mitochondrial electron transport chain, β-oxidation of fatty acids, redox homeostasis, citric acid cycle, branched-chain amino acid catabolism, chromatin remodeling, DNA repair, protein folding, and apoptosis. Unsurprisingly, impairment of flavin homeostasis in humans has been linked to various diseases including neuromuscular and neurological disorders, abnormal fetal development, and cardiovascular diseases. This review presents an overview of riboflavin metabolism, its role in mitochondrial function, primary and secondary flavocoenzyme defects associated with mitochondrial dysfunction, and the role of riboflavin supplementation in these conditions.

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“…However, recurrent optic neuropathy is a feature of other mitochondrial disorders, such as Leber's Hereditary Optic Neuropathy (LHON) and in patients with mitofusin mutations. In addition, acute neurological de cits with MRI features of white matter abnormalities in the brain and spinal cord have been reported in CI de ciency, CIII de ciency due to LYRM7 mutations, mtDNA depletion syndrome and multiple mitochondrial dysfunction syndrome (2). On the other hand, a preliminary assumption of the appearance of demyelination-like lesions such as multiple sclerosis has been proposed in some mitochondrial genomic haplotype variation (16).…”

Section: Discussionmentioning

confidence: 99%

“…Leukodystrophies usually manifest with bilateral, con uent and symmetric abnormal white matter signal changes in brain magnetic resonance imaging (MRI) while asymmetric multifocal lesions usually address the acquired white matter disorders (1) An overlapping clinical and imaging presentations of mitochondrial leukoencephalopathy and acquired demyelinating disorders due to mutation in LYRM7 coding for complex III has been reported (2). Ubiquinol-cytochrome c oxidoreductase or complex III (CIII) is a cardinal unit of mitochondrial oxidative phosphorylation chain, which together with other complexes within the inner membrane of mitochondria generate the required cellular ATP (3).…”

Section: Introductionmentioning

confidence: 99%

Complex III Mitochondrial Leukoencephalopathy Masquerading Acute Demyelinating Syndrome Due to a Novel Variant in CYC1

Heidari

Rasoulinezhad

Pak

et al. 2021

Preprint

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Background Complex III (CIII) is the third out of five mitochondrial respiratory chain complexes residing at the mitochondrial inner membrane. The assembly of 10 subunits encoded by nuclear DNA and one by mitochondrial DNA result in the functional CIII which transfers electrons from ubiquinol to cytochrome c. Deficiencies of CIII are among the least investigated mitochondrial disorders and thus clinical spectrum of patients with mutations in CIII is not well defined. Resultswe report on a 10-year-old girl born to consanguineous Iranian parents presenting with acute neurological deficits reminiscent of acquired demyelination, mainly acute bilateral vision loss, who was ultimately confirmed to have a novel homozygous missense variant, c.949C>T; p.(Arg317Trp) in complex III of the mitochondrial chain. Sanger sequencing confirmed the segregation of this variant with disease in the family. ConclusionWe present a patient with a mitochondrial leukoencephalopathy due to complex III deficiency that manifested with features suggestive of an acquired demyelinating syndrome. The effect of this variant on the protein structure was shown in-silico. Our findings, not only expand the clinical spectrum due to defects in CYC1 gene but also highlight that mitochondrial disease should be considered in children with acute CNS demyelination.

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Mitochondrial leukoencephalopathies: A border zone between acquired and inherited white matter disorders in children?

Cited by 34 publications

References 29 publications

Analysis of Human Mutations in the Supernumerary Subunits of Complex I

Analysis of Human Mutations in the Supernumerary Subunits of Complex I

Riboflavin metabolism: role in mitochondrial function

Complex III Mitochondrial Leukoencephalopathy Masquerading Acute Demyelinating Syndrome Due to a Novel Variant in CYC1

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