bims-symami Biomed News
on Symptom management in mitochondrial disease
Issue of 2023–05–28
nine papers selected by
The Lily Foundation
  1. A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
  2. CRISPR-free, strand-selective mitochondrial DNA base editing using a nickase.
  3. Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD).
  4. Two cases of MT-ND5-related mitochondrial disorder misdiagnosed as seronegative neuromyelitis optica spectrum disorder.
  5. Combined MITOchondrial-NUCLEAR (MITO-NUCLEAR) Analysis for Mitochondrial Diseases Diagnosis: Validation and Implementation of a One-Step NGS Method.
  6. A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt-ND variants.
  7. Strand-selective base editing of human mitochondrial DNA using mitoBEs.
  8. Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.
  9. Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes.
  1. EMBO Mol Med. 2023 May 24. e16951
    A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
    Nneka Southwell, Guido Primiano, Viraj Nadkarni, Nabeel Attarwala, Emelie Beattie, Dawson Miller, Sumaitaah Alam, Irene Liparulo, Yevgeniya I Shurubor, Maria Lucia Valentino, Valerio Carelli, Serenella Servidei, Steven S Gross, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.
      Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
    Keywords:  amino acid metabolism; glucocorticoids; leptin; mitochondrial myopathy; muscle wasting
    DOI:  https://doi.org/10.15252/emmm.202216951
  2. Nat Biotechnol. 2023 May 22.
    CRISPR-free, strand-selective mitochondrial DNA base editing using a nickase.
      
    DOI:  https://doi.org/10.1038/s41587-023-01820-w
  3. Mult Scler. 2023 May 25. 13524585231172950
    Leigh syndrome mimicking neuromyelitis optica spectrum disorder (NMOSD).
    Nee Na Kim, Omar Abdel-Mannan, James Davidson, Pascale Du Pre, Rachel Kneen, Kshitij Mankad, Yael Hacohen.
      We report two children with molecularly confirmed mitochondrial disease mimicking Neuromyelitis Optica Spectrum Disorder (NMOSD). The first patient presented at the age of 15 months with acute deterioration following a pyrexial illness with clinical features localising to the brainstem and spinal cord. The second patient presented at 5 years with acute bilateral visual loss. In both cases, MOG and AQP4 antibodies were negative. Both patients died within a year of symptoms onset from respiratory failure. Arriving at an early genetic diagnosis is important for redirection of care and avoiding potentially harmful immunosuppressant therapies.
    Keywords:  Neuromyelitis optica spectrum disorder; acquired demyelinating syndromes; mitochondrial diseases; neurogenetics
    DOI:  https://doi.org/10.1177/13524585231172950
  4. Mult Scler. 2023 May 25. 13524585231172947
    Two cases of MT-ND5-related mitochondrial disorder misdiagnosed as seronegative neuromyelitis optica spectrum disorder.
    Sophie R Wilkins, Amy W Yu, Connolly Steigerwald, Kurenai Tanji, Alejandro D Iglesias, Michio Hirano, Ilya Kister, Claire S Riley, Nicolas J Abreu.
      Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease primarily affecting the optic nerves and spinal cord, which is usually associated with anti-aquaporin-4 antibodies. Here, we present two individuals who were negative for anti-aquaporin-4 antibodies and were initially diagnosed with seronegative NMOSD. Each patient's clinical course and radiographic features raised suspicion for an alternative disease process. Both individuals were found to have pathogenic variants of MT-ND5, encoding subunit 5 of mitochondrial complex I, ultimately leading to a revised diagnosis of a primary mitochondrial disorder. These cases illustrate the importance of biochemical and genetic testing in atypical cases of NMOSD.
    Keywords:  Neuromyelitis optica; genetics; mitochondrial disease; relapsing/remitting
    DOI:  https://doi.org/10.1177/13524585231172947
  5. Genes (Basel). 2023 May 15. pii: 1087. [Epub ahead of print]14(5):
    Combined MITOchondrial-NUCLEAR (MITO-NUCLEAR) Analysis for Mitochondrial Diseases Diagnosis: Validation and Implementation of a One-Step NGS Method.
    Ferdinando Barretta, Fabiana Uomo, Filomena Caldora, Rossella Mocerino, Daniela Adamo, Francesco Testa, Francesca Simonelli, Olga Scudiero, Nadia Tinto, Giulia Frisso, Cristina Mazzaccara.
       BACKGROUND: Next-generation sequencing (NGS) technology is revolutionizing diagnostic screening for mitochondrial diseases (MDs). Moreover, an investigation by NGS still requires analyzing the mitochondrial genome and nuclear genes separately, with limitations in terms of time and costs. We describe the validation and implementation of a custom blended MITOchondrial-NUCLEAR (MITO-NUCLEAR) assay for the simultaneous identification of genetic variants both in whole mtDNA and in nuclear genes included in a clinic exome panel. Furthermore, the MITO-NUCLEAR assay, implemented in our diagnostic process, has allowed us to arrive at a molecular diagnosis in a young patient.
    METHODS: Massive sequencing strategy was applied for the validation experiments, performed using multiple tissues (blood, buccal swab, fresh tissue, tissue from slide, and formalin-fixed paraffin-embedded tissue section) and two different blend-in ratios of the mitochondrial probes: nuclear probes; 1:900 and 1:300.
    RESULTS: Data suggested that 1:300 was the optimal probe dilution, where 100% of the mtDNA was covered at least 3000×, the median coverage was >5000×, and 93.84% of nuclear regions were covered at least 100×.
    CONCLUSIONS: Our custom Agilent SureSelect MITO-NUCLEAR panel provides a potential "one-step" investigation that may be applied to both research and genetic diagnosis of MDs, allowing the simultaneous discovery of nuclear and mitochondrial mutations.
    Keywords:  MITO-NUCLEAR; combined sequencing of mitochondrial and nuclear DNA; mitochondrial and nuclear disease panel; mitochondrial diseases; mtDNA; next-generation sequencing (NGS); nuclear genes
    DOI:  https://doi.org/10.3390/genes14051087
  6. Ann Clin Transl Neurol. 2023 May 23.
    A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt-ND variants.
    Wei Wang, Yuying Zhao, Xuebi Xu, Xiaotian Ma, Yuan Sun, Yan Lin, Ying Zhao, Zhihong Xu, Jiayin Wang, Hong Ren, Bin Wang, Dandan Zhao, Dongdong Wang, Fuchen Liu, Wei Li, Chuanzhu Yan, Kunqian Ji.
       OBJECTIVE: To explore the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by mitochondrial DNA-encoded complex I subunit (mt-ND) variants.
    METHODS: In this retrospective study, the clinical, myopathological and brain MRI features of patients with MELAS caused by mt-ND variants (MELAS-mtND) were collected and compared with those of MELAS patients carrying the m.3243A > G variant (MELAS-A3243G).
    RESULT: A total of 18 MELAS-mtND patients (female: 7; median age: 24.5 years) represented 15.9% (n = 113) of all patients with MELAS caused by mtDNA variants in our neuromuscular center from January 2012 to June 2022. In this MELAS-mtND cohort, the two most common variants were m.10191 T > C (4/18, 22.2%) and m.13513 G > A (3/18, 16.7%). The most frequent symptoms were seizures (14/18, 77.8%) and muscle weakness (11/18, 61.1%). Compared with 87 MELAS-A3243G patients, MELAS-mtND patients were significantly more likely to have a variant that was absent in blood cells (40% vs. 1.4%). Furthermore, MELAS-mtND patients had a significantly lower MDC score (7.8 ± 2.7 vs. 9.8 ± 1.9); less hearing loss (27.8% vs. 54.0%), diabetes (11.1% vs. 37.9%), and migraine (33.3% vs. 62.1%); less short stature (males ≤ 165 cm; females ≤ 155 cm; 23.1% vs. 60.8%) and higher body mass index (20.4 ± 2.5 vs. 17.8 ± 2.7). MELAS-mtND patients had significantly more normal muscle pathology (31.3% vs. 4.1%) and fewer RRFs/RBFs (62.5% vs. 91.9%), COX-deficient fibers/blue fibers (25.0% vs. 85.1%) and SSVs (50.0% vs. 81.1%). Moreover, brain MRI evaluated at the first stroke-like episode showed significantly more small cortical lesions in MELAS-mtND patients (66.7% vs. 12.2%).
    INTERPRETATION: Our results suggested that MELAS-mtND patients have distinct clinical, myopathological and brain MRI features compared with MELAS-A3243G patients.
    DOI:  https://doi.org/10.1002/acn3.51787
  7. Nat Biotechnol. 2023 May 22.
    Strand-selective base editing of human mitochondrial DNA using mitoBEs.
    Zongyi Yi, Xiaoxue Zhang, Wei Tang, Ying Yu, Xiaoxu Wei, Xue Zhang, Wensheng Wei.
      A number of mitochondrial diseases in humans are caused by point mutations that could be corrected by base editors, but delivery of CRISPR guide RNAs into the mitochondria is difficult. In this study, we present mitochondrial DNA base editors (mitoBEs), which combine a transcription activator-like effector (TALE)-fused nickase and a deaminase for precise base editing in mitochondrial DNA. Combining mitochondria-localized, programmable TALE binding proteins with the nickase MutH or Nt.BspD6I(C) and either the single-stranded DNA-specific adenine deaminase TadA8e or the cytosine deaminase ABOBEC1 and UGI, we achieve A-to-G or C-to-T base editing with up to 77% efficiency and high specificity. We find that mitoBEs are DNA strand-selective mitochondrial base editors, with editing results more likely to be retained on the nonnicked DNA strand. Furthermore, we correct pathogenic mitochondrial DNA mutations in patient-derived cells by delivering mitoBEs encoded in circular RNAs. mitoBEs offer a precise, efficient DNA editing tool with broad applicability for therapy in mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41587-023-01791-y
  8. Antioxidants (Basel). 2023 Apr 26. pii: 1001. [Epub ahead of print]12(5):
    Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.
    Biyi Chen, Nastaran Daneshgar, Hsiang-Chun Lee, Long-Sheng Song, Dao-Fu Dai.
      Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh Syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.
    Keywords:  Leigh Syndrome; arrhythmia; bradycardia; cardiomyopathy; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/antiox12051001
  9. Int J Mol Sci. 2023 May 22. pii: 9108. [Epub ahead of print]24(10):
    Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes.
    Emanuele Monda, Michele Lioncino, Martina Caiazza, Vincenzo Simonelli, Claudia Nesti, Marta Rubino, Alessia Perna, Alfredo Mauriello, Alberta Budillon, Vincenzo Pota, Giorgia Bruno, Antonio Varone, Vincenzo Nigro, Filippo Maria Santorelli, Giuseppe Pacileo, Maria Giovanna Russo, Giulia Frisso, Simone Sampaolo, Giuseppe Limongelli.
      Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.
    Keywords:  cardiomyopathy; genetic testing; neuromuscular disease
    DOI:  https://doi.org/10.3390/ijms24109108
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