bims-curels Biomed News
on Leigh syndrome
Issue of 2024–04–28
six papers selected by
Cure Mito Foundation
  1. Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
  2. Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
  3. Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.
  4. Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
  5. A Case Report of a Clinically Suspected Diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome With Cardiac Impairment.
  6. [Leber's hereditary optic neuropathy].
  1. Eur J Clin Invest. 2024 Apr 21. e14217
    Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
    Kevin Aguilar, Patrycja Jakubek, Antonio Zorzano, Mariusz R Wieckowski.
       OBJECTIVES AND SCOPE: Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.
    INSIGHTS: The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.
    SUMMARY: In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.
    Keywords:  ETC; OXPHOS; bioenergetics; metabolism; mitochondria; mtDNA; nDNA; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.1111/eci.14217
  2. Genes (Basel). 2024 Apr 17. pii: 500. [Epub ahead of print]15(4):
    Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
    Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide, Eirik Frengen.
      Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.
    Keywords:  Alu element; COX; Complex IV; Leigh syndrome; NDUFA4/COXFA4; WGS; encephalopathy; structural variant (SV)
    DOI:  https://doi.org/10.3390/genes15040500
  3. Front Bioeng Biotechnol. 2024 ;12 1372211
    Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.
    Jiaxin Qiu, Haibo Wu, Qin Xie, Yuxiao Zhou, Yining Gao, Junbo Liu, Xueyi Jiang, Lun Suo, Yanping Kuang.
      Introduction: Mitochondrial diseases caused by mtDNA have no effective cures. Recently developed DddA-derived cytosine base editors (DdCBEs) have potential therapeutic implications in rescuing the mtDNA mutations. However, the performance of DdCBEs relies on designing different targets or improving combinations of split-DddA halves and orientations, lacking knowledge of predicting the results before its application. Methods: A series of DdCBE pairs for wide ranges of aC or tC targets was constructed, and transfected into Neuro-2a cells. The mutation rate of targets was compared to figure out the potential editing rules. Results: It is found that DdCBEs mediated mtDNA editing is predictable: 1) aC targets have a concentrated editing window for mtDNA editing in comparison with tC targets, which at 5'C8-11 (G1333) and 5'C10-13 (G1397) for aC target, while 5'C4-13 (G1333) and 5'C5-14 (G1397) for tC target with 16bp spacer. 2) G1333 mediated C>T conversion at aC targets in DddA-half-specific manner, while G1333 and G1397 mediated C>T conversion are DddA-half-prefer separately for tC and aC targets. 3) The nucleotide adjacent to the 3' end of aC motif affects mtDNA editing. Finally, by the guidance of these rules, a cell model harboring a pathogenic mtDNA mutation was constructed with high efficiency and no bystander effects. Discussion: In summary, this discovery helps us conceive the optimal strategy for accurate mtDNA editing, avoiding time- and effort-consuming optimized screening jobs.
    Keywords:  DdCBEs; gene editing; mitochondrial genome; mtDNA; predictability
    DOI:  https://doi.org/10.3389/fbioe.2024.1372211
  4. Cell Death Dis. 2024 Apr 20. 15(4): 281
    Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
    Raquel Brañas Casas, Alessandro Zuppardo, Giovanni Risato, Alberto Dinarello, Rudy Celeghin, Camilla Fontana, Eleonora Grelloni, Alexandru Ionut Gilea, Carlo Viscomi, Andrea Rasola, Luisa Dalla Valle, Tiziana Lodi, Enrico Baruffini, Nicola Facchinello, Francesco Argenton, Natascia Tiso.
      The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.
    DOI:  https://doi.org/10.1038/s41419-024-06622-9
  5. Cureus. 2024 Mar;16(3): e56980
    A Case Report of a Clinically Suspected Diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome With Cardiac Impairment.
    Rabiu Momoh, Sam Kollamparambil.
      This case report presents a description of a hypertrophic left ventricle with reduced ejection fraction in a man in his mid-twenties with clinical, radiologic, and biochemical features of a rare syndrome called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). A literature review of this uncommon syndrome and MELAS cardiomyopathy has been conducted.
    Keywords:  cardiology imaging; cardiomyopathy; genetic syndromes; heart failure; hyperlactatemia; maternal inheritance; melas; melas cardiomyopathy; mitochondrial disorder; rare diseases
    DOI:  https://doi.org/10.7759/cureus.56980
  6. Rinsho Shinkeigaku. 2024 Apr 20.
    [Leber's hereditary optic neuropathy].
    Yasuyuki Takai, Akiko Yamagami, Hitoshi Ishikawa.
      Leber's hereditary optic atrophy (LHON) is a genetic optic neuropathy that is more prevalent in young males but can occur from childhood to old age. The primary cause is mitochondrial genetic mutations, which are associated with dysfunction of mitochondrial electron transport chain complex I. It manifests as acute to subacute visual impairment, often starting unilaterally but progressing to involve both eyes within weeks to months. Visual loss is severe, with many patients having corrected visual acuity below 0.1. The differential diagnosis of optic neuritis is essential, and assessments such as pupillary light reflex, fluorescein fundus angiography, and magnetic resonance imaging can be useful for differentiation. LHON should be considered as one of the differential diagnoses for optic neuritis, and collaboration between neurologists and ophthalmologists is crucial for accurate diagnosis and appropriate treatment.
    Keywords:  Leber’s hereditary optic neuropathy; mitochondrial disease; optic neuritis
    DOI:  https://doi.org/10.5692/clinicalneurol.cn-001924
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:14.