Cerebral imaging in paediatric mitochondrial disorders

Finsterer, Josef; Zarrouk‐Mahjoub, Sinda

doi:10.1177/1971400918786054

Cited by 9 publications

(5 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The question of whether peripheral bioenergetic changes may reflect or be predictive of CNS mitochondrial deficits with links to WMHV and BV changes deserves a separate discussion. There is a clear overlap of features between premutation phenotype and mitochondrial diseases, including WMHs in both cerebral and cerebellar white matter in mitochondrial diseases and FXTAS [62,77,78]. Cerebellar atrophy, particularly affecting children, is another core feature of mitochondrial dysfunction [77].…”

Section: Discussionmentioning

confidence: 99%

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

Wang

Napoli

Kim

et al. 2021

IJMS

View full text Add to dashboard Cite

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings—and the lack of correlations with FXTAS diagnosis/stages—may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.

show abstract

Section: Discussionmentioning

confidence: 99%

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

Wang

Napoli

Kim

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In patients with MELAS syndrome, stroke-like lesions with the involvement of grey matter and subcortical white matter typically exhibit a "shifting spread" (appearance, disappearance and re-appearance). These lesions are characterized by asymmetric signal changes crossing vascular territories and an abnormally prominent lactate peak [37,38]. Some patients also have small lesions in the deep grey matter (either less symmetrical than in LS or unilateral) and calcifications in basal ganglia.…”

Section: Discussionmentioning

confidence: 99%

Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

et al. 2020

View full text Add to dashboard Cite

Background: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. Methods: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. Results: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14 C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. Conclusions: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14 C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.

show abstract

“…Indeed, enhanced interferon signaling related to ATAD3A dysfunction was only recognized six years after gene mutations were initially described ( 77 , 84 , 85 ). Further indication of a possible relationship between mitochondrial disease and the type I interferonopathies comes from shared clinical features, such as intracranial calcification being an established sign in both settings ( 3 , 118 ). Similarly, bilateral striatal necrosis is recurrent in mitochondrial disease, and consistently described in the context of mutations in both PNPT1 ( 78 ) and the type I interferonopathy due to ADAR1 loss-of-function ( 119 ).…”

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

2021

View full text Add to dashboard Cite

The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.

show abstract

Cerebral imaging in paediatric mitochondrial disorders

Abstract: CNS imaging in paediatric MIDs is important for diagnosing and monitoring CNS involvement. It also contributes to the understanding of the underlying pathomechanisms that lead to CNS involvement in MIDs.

Cited by 9 publications

References 131 publications

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Contact Info

Product

Resources

About