bims-symami Biomed News
on Symptom management in mitochondrial disease
Issue of 2023–05–21
thirteen papers selected by
The Lily Foundation
  1. Molecular analysis of gene variants in an Iranian family with psychomotor retardation mitochondrial disorder patient.
  2. Recent advances and new perspectives in mitochondrial dysfunction.
  3. First baby born in the UK using mitochondrial donation therapy.
  4. Long-term ketogenic diet therapy improves mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS): A case report.
  5. Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
  6. The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases.
  7. Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.
  8. [Therapeutics for Mitochondrial Encephalomyopathy].
  9. Hepatic presentations of mitochondrial DNA depletion syndrome in children - a single tertiary liver centre experience.
  10. New avenues for therapy in mitochondrial optic neuropathies.
  11. Combined Clinical, Molecular, and Muscle Biopsy Approach to Unveil Prevalence and Clinical Features of Rare Neuromuscular and Mitochondrial Diseases in Patients With Cardiomyopathies.
  12. Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.
  13. Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
  1. Clin Case Rep. 2023 May;11(5): e7308
    Molecular analysis of gene variants in an Iranian family with psychomotor retardation mitochondrial disorder patient.
    Forough Shabannejadian, Seyedeh Zahra Masoomizadeh, Behnaz Andashti.
      In 1-year-old girl presenting with neurodegenerative mitochondrial disease (Leigh syndrome), mutation analysis was performed by whole exome sequencing. Pathogenic variants were then analyzed in parents and relatives by Sanger sequencing. We identified a point mutation c.G484A in NDUFS8 gene which was homozygous in patient and heterozygous in parents.
    Keywords:  Leigh syndrome; mitochondrial disease; whole exome sequencing
    DOI:  https://doi.org/10.1002/ccr3.7308
  2. Sci Rep. 2023 May 17. 13(1): 7977
    Recent advances and new perspectives in mitochondrial dysfunction.
    Cecilia Giulivi, Kezhong Zhang, Hirofumi Arakawa.
      
    DOI:  https://doi.org/10.1038/s41598-023-34624-8
  3. BMJ. 2023 05 12. 381 1091
    First baby born in the UK using mitochondrial donation therapy.
    Jacqui Wise.
      
    DOI:  https://doi.org/10.1136/bmj.p1091
  4. CNS Neurosci Ther. 2023 May 19.
    Long-term ketogenic diet therapy improves mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS): A case report.
    Fang He, Lingqi Ye, Pu Miao, Jiong Zhou, Yao Ding, Shuang Wang.
      
    Keywords:  MELAS syndrome; epileptic seizures; ketogenic diet
    DOI:  https://doi.org/10.1111/cns.14274
  5. Eye (Lond). 2023 Apr 25.
    Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
    Benson S Chen, Joshua P Harvey, Michael J Gilhooley, Neringa Jurkute, Patrick Yu-Wai-Man.
      Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.
    DOI:  https://doi.org/10.1038/s41433-023-02523-x
  6. Acta Neurol Taiwan. 2023 Jun 30. 32(2) 74-78
    The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases.
    Mahtab Ramezani, Mohammad Mahdi Rabiei, Zahra Cheraghi, Leila Simani.
       BACKGROUND: During corona virus pandemic, various neurological complications of COVID-19 have been reported. Recent studies demonstrated different pathophysiology for neurological manifestations of COVID-19 such as mitochondrial dysfunction and damage to cerebral vasculature. In addition, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder with a variety of neurological symptoms. In this study, we aim to assess a potential predisposition in mitochondrial dysfunction of COVID-19, leading to MELAS presentation.
    METHODS: We studied three previously healthy patients with the first presentation of acute stroke-like symptoms, following COVID-19 infection. We analyzed the patients' clinical data and brain magnetic resonance imaging (MRI) lesions that presented to the neurological center of a university-affiliated hospital in Tehran, Iran, from September 2020 to August 2021.
    RESULTS: All cases are characterized by a temporoparietal abnormality in imaging studies and electroencephalogram (EEG). Based on electrodiagnostic tests, three patients were diagnosed with myopathy. In two brothers with relatively the same symptoms, one performed muscle biopsy finding myopathic process, and genetic testing confirmed a 3243A>G point mutation in a heteroplasmic state in one of our patients.
    CONCLUSION: Although MELAS is not a prevalent condition, the recent increase in the number of these patients in our center might indicate the potential role of COVID-19 in triggering the silent pre- existing mitochondrial dysfunction in these patients.
    Keywords:  COVID-19; MELAS; Stroke-like episode Mitochondrial dysfunction.
  7. Clin Transl Sci. 2023 May 12.
    Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.
    Sebastiaan J W van Kraaij, Diana R Pereira, Bastiaan Smal, Luciana Summo, Anne Konkel, Janine Lossie, Andreas Busjahn, Tom N Grammatopoulos, Erica Klaassen, Robert Fischer, Wolf-Hagen Schunck, Pim Gal, Matthijs Moerland.
      The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF-15, IL-6, NT-proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide-adenine-dinucleotide-hydrogen (NADH) content in skin as well as reduced passive leg movement-induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood-based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis.
    DOI:  https://doi.org/10.1111/cts.13530
  8. Brain Nerve. 2023 May;75(5): 523-525
    [Therapeutics for Mitochondrial Encephalomyopathy].
    Yoshihide Sunada.
      In MELAS, taurine modification defect in the anticodon of mitochondrial leucine tRNA causes codon translation failure. An investigator-started clinical trials of high-dose taurine therapy, that showed its efficacy in preventing stroke-like episodes, and improving the taurine modification rate. The drug was found to be safe. Taurine has been approved as a drug covered by public insurance for prevention of stroke-like episodes since 2019. Recently, L-arginine hydrochloride has also been approved for off-label use as a treatment for both acute and intermittent stages of stroke-like episodes.
    DOI:  https://doi.org/10.11477/mf.1416202371
  9. J Inherit Metab Dis. 2023 May 19.
    Hepatic presentations of mitochondrial DNA depletion syndrome in children - a single tertiary liver centre experience.
    R Vara, M Pinon, C Fratter, R Hegarty, N Hadzic.
      
    DOI:  https://doi.org/10.1002/jimd.12633
  10. Ther Adv Rare Dis. 2021 Jan-Dec;2:2 26330040211029037
    New avenues for therapy in mitochondrial optic neuropathies.
    Wing Sum Vincent Ng, Matthieu Trigano, Thomas Freeman, Carmine Varrichio, Dinesh Kumar Kandaswamy, Ben Newland, Andrea Brancale, Malgorzata Rozanowska, Marcela Votruba.
      Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.
    Plain language summary: Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.
    Keywords:  LHON; OPA1; mitochondria; mitochondrial dysfunction; optic neuropathy; therapy
    DOI:  https://doi.org/10.1177/26330040211029037
  11. Circ Genom Precis Med. 2023 May 17. e004122
    Combined Clinical, Molecular, and Muscle Biopsy Approach to Unveil Prevalence and Clinical Features of Rare Neuromuscular and Mitochondrial Diseases in Patients With Cardiomyopathies.
    Michele Lioncino, Emanuele Monda, Martina Caiazza, Vincenzo Simonelli, Claudia Nesti, Alfredo Mauriello, Alberta Budillon, Alessandro Di Santo, Giorgia Bruno, Antonio Varone, Vincenzo Nigro, Filippo Maria Santorelli, Giuseppe Pacileo, Maria Giovanna Russo, Giulia Frisso, Simone Sampaolo, Giuseppe Limongelli.
      
    Keywords:  biopsy; cardiomyopathies; cardiovascular disease; mitochondrial disease; morbidity
    DOI:  https://doi.org/10.1161/CIRCGEN.123.004122
  12. MedComm (2020). 2023 Jun;4(3): e217
    Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.
    Wenzhi Li, Xiaoyu Liao, Kaibo Lin, Renfei Cai, Haiyan Guo, Meng Ma, Yao Wang, Yating Xie, Shaozhen Zhang, Zhiguang Yan, Jiqiang Si, Hongyuan Gao, Leiwen Zhao, Li Chen, Weina Yu, Chen Chen, Yun Wang, Yanping Kuang, Qifeng Lyu.
      The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle-protrusion-retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal-karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live-born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.
    Keywords:  assisted reproductive technology; mitochondrial disease inheritance; mitochondrial genetic drift; mitochondrial replacement therapy; second polar body transfer
    DOI:  https://doi.org/10.1002/mco2.217
  13. J Transl Med. 2023 May 19. 21(1): 331
    Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
    Emily B Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Melissa L Schlein, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.
       BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.
    METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways.
    RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction.
    CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
    Keywords:  Anti-viral signaling; Inflammation; Interferon; Mitochondrial disease; PBMCs
    DOI:  https://doi.org/10.1186/s12967-023-04180-w
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