Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant

Abstract

HighlightsNovel mt-tRNASer(UCN) (m.7486G>A) variant found in CPEO patient with 4,977 bp deletion.The variant located in the anticodon loop meets the pathogenicity criteria.Both genetic defects segregate with the biochemical phenotype in muscle.Assembly impairment of MRC complexes was detected.Mitochondrial translation defect and bioenergetic dysfunction were revealed.

Proteomics of Cytochrome c Oxidase-Negative versus -Positive Muscle Fiber Sections in Mitochondrial Myopathy

“…We measured a significant increase of several members of the OPA1-dependent cristae remodeling program in COX À single slow fibers, suggesting that they may be producing more cristae. Ultrastructural analyses of patients with CPEO and other mitochondrial disorders show several morphological abnormalities, such as extended ''onion-like'' concentric cristae and ''donut mitochondria,'' indicating elongation and hyperbranching (Bacalhau et al, 2018;Vincent et al, 2016). Because the ultimate effects of mtDNA mutations will reflect on the fiber metabolic profile, it would be interesting to carry out a metabolomic analysis of COX + and COX À fibers following the technological progress of this field.…”

Chronic progressive external ophthalmoplegia in a Saudi patient with a mutation in the POLG gene successfully managed with bilateral frontalis sling

“…Muscle biopsies in patients with CPEO typically show a subsarcolemmal accumulation of ragged-red fibers (abnormal mitochondria) and a mosaic pattern of COX-deficient fibers with abnormal COX activity. The abnormal mitochondrial changes occur when the accumulation of mutated mitochondrial DNA exceeds a biochemical threshold (threshold effect) [14]. In our patient, a muscle biopsy was normal with a lack of ragged-red fibers, which are considered to be the morphological hallmark of mitochondrial myopathy.…”

A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity

“…[28] The exact roles of co-segregated mtDNA variants cannot be robustly determined in some patients, leading to speculation of a synergistic, pathogenic effect or that one of the mtDNA variants may act to modulate the penetrance of the second mtDNA variant. [29][30][31][32] On the other hand, some of these variants can be classified as neutral polymorphisms retrospectively when more stringent diagnostic criteria have been applied. [33][34][35] Our case study is unique as we have established that only the de novo m.7887G>A variant is pathogenic, whilst the maternallyinherited m.8250G>A variant is a polymorphism through the analysis of the patient's and his mother's muscle biopsies.…”

“…In some cases, the co-presence of two pathogenic mtDNA variants was thought to contribute the clinical manifestations, such as identification of m.11778G>A and a single, large-scale mtDNA deletion – the so-called “common mtDNA deletion” - in a young man who with childhood-onset CPEO who later developed symptomatic, bilateral optic neuropathy [27] ; co-existence of single, large-scale deletion and m.3243A>G has also been reported in a woman with Kearns-Sayre syndrome and multiple endocrine disorder [28] . The exact roles of co-segregated mtDNA variants cannot be robustly determined in some patients, leading to speculation of a synergistic, pathogenic effect or that one of the mtDNA variants may act to modulate the penetrance of the second mtDNA variant [29] , [30] , [31] – 32] . On the other hand, some of these variants can be classified as neutral polymorphisms retrospectively when more stringent diagnostic criteria have been applied [33] , [34] – 35] .…”