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Frontiers in Neurology 2023Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy that is characterized by progressive ptosis and impaired ocular motility. Owing...
Have one's view of the important overshadowed by the trivial: chronic progressive external ophthalmoplegia combined with unilateral facial nerve injury: a case report and literature review.
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy that is characterized by progressive ptosis and impaired ocular motility. Owing to its nonspecific clinical manifestations, CPEO is often misdiagnosed as other conditions. Herein, we present the case of a 34-year-old woman who primarily presented with incomplete left eyelid closure and limited bilateral eye movements. During the 6-year disease course, she was diagnosed with myasthenia gravis and cranial polyneuritis. Finally, skeletal muscle tissue biopsy confirmed the diagnosis. Biopsy revealed pathological changes in mitochondrial myopathy. Furthermore, mitochondrial gene testing of the skeletal muscle revealed a single chrmM:8469-13447 deletion. In addition, we summarized the findings of 26 patients with CPEO/Kearns-Sayre syndrome who were misdiagnosed with other diseases owing to ocular symptoms. In conclusion, we reported a rare clinical case and emphasized the symptomatic diversity of CPEO. Furthermore, we provided a brief review of the diagnosis and differential diagnosis of the disease.
PubMed: 38249737
DOI: 10.3389/fneur.2023.1268053 -
Nature Metabolism Feb 2024Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce...
Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII activity in skeletal muscle. We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. This metabolon maintains total Q levels, minimizes QH-reductive stress and improves OXPHOS efficiency. Muscle-specific Etfdh mice develop myopathy due to CIII dysfunction, indicating that ETFDH is a required OXPHOS component and a potential therapeutic target for mitochondrial redox medicine.
Topics: Animals; Mice; Electron-Transferring Flavoproteins; Homeostasis; Lipids; Muscle, Skeletal; Oxidative Phosphorylation; Ubiquinone
PubMed: 38243131
DOI: 10.1038/s42255-023-00956-y -
Neurotherapeutics : the Journal of the... Jan 2024This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach... (Review)
Review
This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
Topics: Humans; Child; Mitochondrial Myopathies; Mitochondria; High-Throughput Nucleotide Sequencing; Mitochondrial Diseases
PubMed: 38241155
DOI: 10.1016/j.neurot.2023.11.001 -
Acta Neuropathologica Jan 2024Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and...
Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.
Topics: Humans; Male; Female; Myotonic Dystrophy; Cross-Sectional Studies; Proteomics; RNA; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 38240888
DOI: 10.1007/s00401-023-02673-y -
Neurology. Clinical Practice Feb 2024Primary mitochondrial myopathies are genetic disorders that primarily affect peripheral skeletal muscles. Patients with primary mitochondrial myopathies often experience...
BACKGROUND AND OBJECTIVES
Primary mitochondrial myopathies are genetic disorders that primarily affect peripheral skeletal muscles. Patients with primary mitochondrial myopathies often experience muscle weakness, fatigue, and other significant impacts on health-related quality of life. The aim of this noninterventional qualitative study was to collect the most bothersome fatigue-related symptoms and impacts reported by patients with primary mitochondrial myopathies and determine whether the questions included in an existing patient-reported outcome measure, the Modified Fatigue Impact Scale, are relevant and interpretable for this population.
METHODS
The interviews contained a concept elicitation exercise to understand the most bothersome primary mitochondrial myopathies symptoms and impacts and a cognitive debriefing section to review the questions included in the Modified Fatigue Impact Scale for relevance and interpretability. Transcripts were coded using ATLAS.ti software.
RESULTS
Interviews were conducted with 16 patients who were aged 16 years and older with a genetically confirmed and clinical diagnosis of symptomatic primary mitochondrial myopathies. Concept elicitation interviews established that while patients with mitochondrial myopathies reported a wide variety of symptoms and impacts, one of the most impactful symptoms discussed was fatigue. Cognitive debriefing interview results confirmed that the Modified Fatigue Impact Scale items were relevant, were interpretable, and largely captured patients' experience with fatigue.
DISCUSSION
Fatigue was one of the most widely discussed experiences discussed by participants and was considered the most important symptom/impact to treat by most of the participants. The Modified Fatigue Impact Scale could be used in future clinical trials to measure treatment benefit in fatigue-related impacts.
PubMed: 38229875
DOI: 10.1212/CPJ.0000000000200229 -
Cureus Dec 2023Patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a mitochondrial disease, develop various types of organ failure,...
Improvement of Intestinal Pseudo-Obstruction by Total Parenteral Nutrition in a Young Woman With Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Case Report.
Patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a mitochondrial disease, develop various types of organ failure, including intestinal pseudo-obstruction (IPO). We treated a patient with IPO that improved with total parenteral nutrition. A 20-year-old woman with a two-year history of diabetes mellitus was taking sitagliptin but her hemoglobin A1c (HbA1c) levels began increasing. After receiving metformin, she suffered a stroke-like attack and was diagnosed with MELAS. After persistent anorexia, she presented with symptoms of IPO, such as vomiting and gastrointestinal dilatation. After about 10 days of total parenteral nutrition, intestinal peristalsis improved and bowel movements resumed. She was able to resume her normal diet, and glycemic control with insulin glargine has allowed her to return to her daily life without gastrointestinal symptoms for over six months. Total parenteral nutrition may be effective for MELAS with IPO, and good glycemic control can prevent the need for incretin-related drugs, thus reducing the likelihood of recurrent IPO.
PubMed: 38186459
DOI: 10.7759/cureus.50075 -
Hepatology Communications Jan 2024Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from...
BACKGROUND
Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children.
METHODS
Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls.
RESULTS
GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01).
CONCLUSIONS
GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.
Topics: Child; Humans; Alagille Syndrome; Biliary Atresia; Biomarkers; Growth Differentiation Factor 15; Non-alcoholic Fatty Liver Disease; Mitochondrial Diseases
PubMed: 38180987
DOI: 10.1097/HC9.0000000000000361 -
Neurology India 2023Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant,...
OBJECTIVES
Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking.
MATERIALS AND METHODS
Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies.
RESULTS
Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness.
CONCLUSION
We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.
Topics: Humans; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Ophthalmoplegia, Chronic Progressive External; Electromyography; Biopsy
PubMed: 38174457
DOI: 10.4103/0028-3886.391399 -
Stem Cell Research & Therapy Jan 2024Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients...
BACKGROUND
Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models.
METHODS
To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DES mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DES mutation, and post-mortem heart samples from five control healthy donors.
RESULTS
The heterozygous DES mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.
CONCLUSIONS
This work highlights the deleterious effects of DES mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
Topics: Humans; Desmin; Induced Pluripotent Stem Cells; Cardiomyopathies; Mutation; Myocytes, Cardiac; Mitochondria
PubMed: 38167524
DOI: 10.1186/s13287-023-03619-7 -
Sultan Qaboos University Medical Journal Dec 2023With the focus on an idiographic approach whereby the observations incorporated the various dimensions of individual functioning 'top-down' to 'bottom-up', this case...
With the focus on an idiographic approach whereby the observations incorporated the various dimensions of individual functioning 'top-down' to 'bottom-up', this case report describes the successful management of a 14-year-old girl with Kearns-Sayre syndrome and Dyggve-Melchior-Clausen disease requiring a transvenous permanent pacemaker implantation for complete heart block. The patient presented to a tertiary care centre in Muscat, Oman, in 2023 seeking consultation. The current idiographic approach appears to have a heuristic value for 2 interrelated reasons. Firstly, it is unlikely that even tertiary care units can accrue such rare presentations and scrutinise them under nomothetic approach. Secondly, by employing the idiographic approach that is capable of examining each case in-depth, the aspiration for good health and well-being may come to the forefront. To the best of the authors' knowledge this is the first published idiographic report in anaesthesia care.
Topics: Female; Humans; Adolescent; Kearns-Sayre Syndrome; Propofol; Dwarfism; Oman
PubMed: 38161763
DOI: 10.18295/squmj.12.2023.080