bims-curels 2024-08-11 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–08–11
ten papers selected by
Cure Mito Foundation

Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.
The clinical and genetic spectrum of mitochondrial diseases in China: A multicenter retrospective cross-sectional study.
Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.
A Method for Producing Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Leigh Syndrome Patients for Its Application in Disease Modeling and Drug Validation.
A Comprehensive Review of Leber Hereditary Optic Neuropathy and Its Association with Multiple Sclerosis-Like Phenotypes Known as Harding's Disease.
The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease.
Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function.
Patient partner perspectives on compensation: Insights from the Canadian Patient Partner Survey.
Knowledge-based representation: Patient engagement in drug development.
Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.

J Clin Res Pediatr Endocrinol. 2024 Aug 08.

Endocrine Disorders in Children with Primary Mitochondrial Diseases: Single-Center Experience.

Esra Deniz Papatya Çakır, Melike Ersıoy, Nihan Çakır Biçer, Asuman Gedikbaşı.

   Objective: Endocrine abnormalities may represent the only clinical manifestation of primary mitochondrial disorders. This study aimed to evaluate the endocrinological characteristics of mitochondrial disease in our cohort.
Methods: A total of twenty-six pediatric patients diagnosed with mitochondrial disease were categorized on the basis of their specific genetic abnormalities. The auxologic data, pubertal development, and, based on their clinical symptoms, hormonal profiles were obtained.
Results: Twelve of the cohort of 26 patients (46%) were female. In 15 of the patients (57.6%), their mitochondrial disease (MD) was caused by nuclear DNA mutations (nDNA group). Four patients had Leigh syndrome, 2 patients had LHON syndrome, 2 patients had MELAS, and 1 patient had KSS clinical phenotype. The median age at diagnosis was 2.91 (0.59-16.8) years, and the median age at first endocrinologic evaluation was 4.62 (1.26-18) years. The mean height SDS was -1.34 ± 2.12, and the mean BMI SDS was -0.82 ± 1.96 for all patients. Of the 26 patients, 6 (23%) had a range of hormonal deficits. Ovarian insufficiency, central adrenal insufficiency, central hypothyroidism, diabetes mellitus, and critical illness-related adrenal insufficiency were all observed. Three of the patients were initially monitored in the endocrine clinic for hormone deficiencies but it was later determined that the hormonal abnormalities were caused by underlying mitochondrial disease.
Conclusion: Individuals diagnosed with mitochondrial disease, particularly those with specific genetic abnormalities, are considered a high-risk group for developing hormonal deficits. Endocrine diseases could be one of the primary mitochondrial disorders' early warning symptoms.

Keywords:  Endocrin abnormalities; Endocrine disorders; Primary mitochondrial disease; genotype-phenotype

DOI:  https://doi.org/10.4274/jcrpe.galenos.2024.2024-1-11
Clin Genet. 2024 Aug 09.

The clinical and genetic spectrum of mitochondrial diseases in China: A multicenter retrospective cross-sectional study.

Yang Zhao, Xutong Zhao, Kunqian Ji, Junling Wang, Yuying Zhao, Jie Lin, Qiang Gang, Meng Yu, Yun Yuan, Haishan Jiang, Chong Sun, Fang Fang, Chuanzhu Yan, Zhaoxia Wang.

  Mitochondrial diseases (MtDs) present diverse clinical phenotypes, yet large-scale studies are hindered by their rarity. This retrospective, multicenter study, conducted across five Chinese hospitals' neurology departments from 2009 to 2019, aimed to address this gap. Nationwide, 1351 patients were enrolled, with a median onset age of 14.0 (18.5) years. The predominant phenotype was mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (45.0%). Mitochondrial DNA (mtDNA) mutations were prevalent (87.4%), with m.3243A>G being the most common locus (48.7%). Meanwhile, POLG mutations in nuclear DNA (nDNA) accounted for 16.5%. Comparative analysis based on age groups (with a cut-off at 14 years) revealed the highest prevalence of MELAS, with Leigh syndrome (LS) and chronic progressive external ophthalmoplegia (CPEO) being the second most common phenotypes in junior and senior groups, respectively. Notably, the most commonly mutated nuclear genes varied across age groups. In conclusion, MELAS predominated in this Chinese MtD cohort, underscored by m.3243A>G and POLG as principal mtDNA mutations and pathogenic nuclear genes. The phenotypic and genotypic disparities observed among different age cohorts highlight the complex nature of MtDs.

Keywords:  genotype; heterogeneity; mitochondrial diseases; phenotype

DOI:  https://doi.org/10.1111/cge.14605
Mol Syndromol. 2024 Aug;15(4): 333-338

Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.

Halil Tuna Akar, Esra Sayar, Özlem Sarıtaş Nakip, Esra Sönmez, Mehmet Burak Özkan, Asburçe Olgaç.

   Introduction: Leigh syndrome is a rare mitochondrial disorder characterized by subacute necrotizing encephalomyelopathy, resulting from defects in mitochondrial respiratory enzymes or pyruvate dehydrogenase complex. Symptoms can manifest in infancy, childhood, or adulthood. We present a case of a 7-month-old girl initially misdiagnosed with septic shock but was later found to have Leigh encephalomyelopathy due to MT-ATP6 deficiency.
Case Presentation: A 7-month-old girl was admitted with fever, drowsiness, and wheezing, initially diagnosed with septic shock. She had a history of parental consanguinity and hypotonia. Physical examination revealed unconsciousness, miotic pupils, and respiratory distress. Initial laboratory tests showed significant metabolic acidosis and elevated lactate, creatine kinase, and ammonia levels. The patient was treated for sepsis and shock, but her condition worsened with elevated lactate and liver transaminases, eventually leading to hypertrophic cardiomyopathy and multiorgan failure. Her basic metabolic scans showed extremely low citrulline levels, whole-exome sequencing analysis did not show any pathologic change in nuclear genome, and mitochondrial genome analysis revealed an MT-ATP homoplasmic variant. She passed away on the 22nd day of hospitalization.
Discussion/Conclusion: While mitochondrial disorders are broadly acknowledged for their phenotypic diversity, it is essential to note that specific disorders, such as Leigh syndrome, display distinctive presentations with varying degrees of severity. Factors such as the percentage of homoplasmy contribute to the variability in manifestations. Notably, MT-ATP6-associated Leigh syndrome is predominantly characterized by an early onset, typically occurring before the age of 2 years. Low citrulline levels have been observed in approximately 90% of patients with MT-ATP6-related disorders, distinguishing them from other mitochondrial disorders. The exact mechanisms underlying this specific metabolic alteration are not fully understood, but it could be linked to disruptions in the mitochondrial energy production process. The mitochondria are essential for various metabolic pathways, including the urea cycle, where citrulline is involved. The association between low citrulline levels and MT-ATP6-related disorders raises the possibility of using citrulline as a potential biomarker for disease identification. MT-ATP6 defects should be kept in mind in cases with mitochondrial disease and low plasma citrulline levels.

Keywords:  Inborn errors of metabolism; Leigh’s syndrome; Mitochondrial disorders

DOI:  https://doi.org/10.1159/000536676
Methods Mol Biol. 2024 ;2835 121-133

A Method for Producing Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Leigh Syndrome Patients for Its Application in Disease Modeling and Drug Validation.

Keshav Narayan Alagarsamy, Abhay Srivastava, Sanjiv Dhingra.

  Leigh syndrome (LS), a complex multisystemic disorder, poses significant challenges in genetic medicine due to its intricate pathogenesis and wide-ranging clinical manifestations. Notably, these arise from mutations in either nuclear genetic DNA or mitochondrial DNA, affecting ATP production and resulting in diverse clinical outcomes. The unpredictable trajectory of this disease, ranging from severe developmental delays to early mortality, underscores the need for improved therapeutic solutions. This research pivots toward the novel use of induced pluripotent stem cells (iPSCs) as a promising platform for understanding disease mechanisms and spearheading patient-specific drug discoveries. Given the past successes of iPSCs in delineating organ-specific disorders and the recent endorsement of human iPSC-derived cardiomyocytes (CMs) by the FDA for drug evaluation, our work seeks to bridge this innovation to Leigh syndrome research. We detail a methodological approach to generate iPSCs from LS patients and differentiate them into iPSCs-CMs. Using multi-electrode array (MEA) analyses, we evaluate the field potential of these cells, spotlighting the potential of hiPSC-CM in drug validation and disease modeling. This pioneering approach offers a glimpse into the future of patient-centric therapeutic interventions for Leigh/Leigh-like syndrome.

Keywords:  Cardiomyocyte differentiation; Disease modeling; Drug validation; Induced pluripotent stem cells; Leigh Syndrome; Mitochondrial disorder

DOI:  https://doi.org/10.1007/978-1-0716-3995-5_11
Eye Brain. 2024 ;16 17-24

A Comprehensive Review of Leber Hereditary Optic Neuropathy and Its Association with Multiple Sclerosis-Like Phenotypes Known as Harding's Disease.

Jehad Alorainy, Yara Alorfi, Rustum Karanjia, Nooran Badeeb.

  Leber Hereditary Optic Neuropathy (LHON) stands as a distinctive maternally inherited mitochondrial disorder marked by painless, subacute central vision loss, primarily affecting young males. This review covers the possible relationship between LHON and multiple sclerosis (MS), covering genetic mutations, clinical presentations, imaging findings, and treatment options. LHON is associated with mutations in mitochondrial DNA (mtDNA), notably m.11778G>A, m.3460G>A, and m.14484T>C, affecting complex I subunits. Beyond ocular manifestations, LHON can go beyond the eye into a multi-systemic disorder, showcasing extraocular abnormalities. Clinical presentations, varying in gender prevalence and outcomes, underscore the nature of mitochondrial optic neuropathies. Hypotheses exploring the connection between LHON and MS encompass mitochondrial DNA mutations triggering neurological diseases, immunologically mediated responses inducing demyelination, and the possibility of coincidental diseases. The research on mtDNA mutations among MS patients sheds light on potential associations with specific clinical subgroups, offering a unique perspective into the broader landscape of MS. Imaging findings, ranging from white matter alterations to cerebrospinal fluid biomarkers, further emphasize shared pathological processes between LHON-MS and classical MS. This comprehensive review contributes to the understanding of the complex relationship between LHON and MS.

Keywords:  demyelination diseases; mitochondrial DNA; neuro-ophthalmology; visual impairment

DOI:  https://doi.org/10.2147/EB.S470184
Front Pharmacol. 2024 ;15 1428242

The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease.

Kassandra A Zachos, Jann Aldrin Gamboa, Aleena S Dewji, Jocelyn Lee, Sonya Brijbassi, Ana C Andreazza.

  The various roles of the mitochondria and the microbiome in health and disease have been thoroughly investigated, though they are often examined independently and in the context of chronic disease. However, the mitochondria and microbiome are closely connected, namely, through their evolution, maternal inheritance patterns, overlapping role in many diseases and their importance in the maintenance of human health. The concept known as the "mitochondria-microbiome crosstalk" is the ongoing bidirectional crosstalk between these two entities and warrants further exploration and consideration, especially in the context of primary mitochondrial disease, where mitochondrial dysfunction can be detrimental for clinical manifestation of disease, and the role and composition of the microbiome is rarely investigated. A potential mechanism underlying this crosstalk is the role of metabolites from both the mitochondria and the microbiome. During digestion, gut microbes modulate compounds found in food, which can produce metabolites with various bioactive effects. Similarly, mitochondrial metabolites are produced from substrates that undergo biochemical processes during cellular respiration. This review aims to provide an overview of current literature examining the mitochondria-microbiome crosstalk, the role of commonly studied metabolites serve in signaling and mediating these biochemical pathways, and the impact diet has on both the mitochondria and the microbiome. As a final point, this review highlights the up-to-date implications of the mitochondria-microbiome crosstalk in mitochondrial disease and its potential as a therapeutic tool or target.

Keywords:  diet; microbiome; mitochondria; mitochondria-microbiome crosstalk; mitochondrial disease

DOI:  https://doi.org/10.3389/fphar.2024.1428242
Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102257

Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function.

Ju Hyuen Cha, Seok-Hoon Lee, Yejin Yun, Won Hoon Choi, Hansol Koo, Sung Ho Jung, Ho Byung Chae, Dae Hee Lee, Seok Jae Lee, Dong Hyun Jo, Jeong Hun Kim, Jae-Jin Song, Jong-Hee Chae, Jun Ho Lee, Jiho Park, Jin Young Kang, Sangsu Bae, Sang-Yeon Lee.

  Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.

Keywords:  MT: RNA/ DNA editing; NG-ABE8e; NG-ABE8eWQ; NG-Cas9-based ABE8e; NG-Cas9-based ABE8eWQ; SSBP1; editing efficacy; mitochondrial diseases; myopathy; off-target effects; optic atrophy; sensorineural deafness; single-stranded binding protein 1

DOI:  https://doi.org/10.1016/j.omtn.2024.102257
Health Expect. 2024 Feb;27(1): e13971

Patient partner perspectives on compensation: Insights from the Canadian Patient Partner Survey.

Roma Dhamanaskar, Laura Tripp, Meredith Vanstone, Carolyn Canfield, Mary Anne Levasseur, Julia Abelson.

   INTRODUCTION: There is a growing role for patients, family members and caregivers as consultants, collaborators and partners in health system settings in Canada. However, compensation for this role is not systematized. When offered, it varies in both type (e.g., one-time honorarium, salary) and amount. Further, broad-based views of patient partners on compensation are still unknown. We aimed to describe the types and frequency of compensation patient partners have been offered and their attitudes towards compensation.
METHODS: This study uses data from the Canadian Patient Partner Study (CPPS) survey. The survey gathered the experiences and perspectives of those who self-identified as patient partners working across the Canadian health system. Three questions were about compensation, asking what types of compensation participants had been offered, if they had ever refused compensation, and whether they felt adequately compensated. The latter two questions included open-text comments in addition to menu-based and scaled response options. Basic frequencies were performed for all questions and open-text comments were analyzed through inductive qualitative content analysis.
RESULTS: A total of 603 individuals participated in the CPPS survey. Most respondents were never or rarely offered salary (81%), honorarium (64%), gift cards (80%) or material gifts (93%) while half were offered conference registration and expenses at least sometimes. A total of 129 (26%) of 499 respondents reported refusing compensation. Of 511 respondents, half felt adequately compensated always or often, and half only sometimes, rarely or never. Open-text comments revealed positive, ambivalent and negative attitudes towards compensation. Attitudes were framed by perceptions about their role, sentiments of giving back to the health system, feelings of acknowledgement, practical considerations, values of fairness and equity and accountability relationships.
CONCLUSIONS: Our findings confirm that compensation is not standardized in Canada. Half of survey respondents routinely feel inadequately compensated. Patient partners have diverse views of what constitutes adequate compensation inclusive of personal considerations such as a preference for volunteering, and broader concerns such as promoting equity in patient partnership. Organizations should attempt to ensure that compensation practices are clear, transparent and attentive to patient partners' unique contexts.
PATIENT CONTRIBUTION: Two patient partners are members of the CPPS research team and have been fully engaged in all study phases from project conception to knowledge translation. They are co-authors of this manuscript. The survey was co-designed and pilot tested with patient partners and survey participants were patient partners.

Keywords:  compensation; health policy; healthcare; patient engagement; patient involvement; patient partnership

DOI:  https://doi.org/10.1111/hex.13971
Health Expect. 2024 Feb;27(1): e13912

Knowledge-based representation: Patient engagement in drug development.

Claudia Egher, Olga Zvonareva.

   INTRODUCTION: Recently, different actors have intensified their efforts to make drug development more participatory. They have produced many frameworks, tools and dedicated fora, where patients are portrayed as relevant stakeholders to be involved throughout the entire drug development trajectory. To better understand what such participatory efforts entail, in this article, we investigate how patient representation is configured in drug development and what patients can engage as representatives in this field.
METHODS: This is a qualitative study based on the thematic analysis of 40 semistructured interviews with different stakeholders in the field and three patient engagement How-To guides (HTGs) complemented by observations of two sessions of the Patient Engagement Open Forum (PEOF) and a patient expert training of the European Patients' Academy on Therapeutic Innovation (EUPATI).
FINDINGS: The emerging practices of patient engagement in drug development configure representation as hinging upon three types of knowledge-drug development knowledge, autobiographical knowledge and community knowledge-and a specific set of skills. We discern a new kind of representation based on these findings, termed 'knowledge-based representation', which appears to more accurately describe how patients are expected to represent others in drug development.
CONCLUSION: Even though knowledge-based representation may be understood as an attempt to downplay the political aspects of representation in favour of its epistemic elements, the political processes involved in patient representation in drug development cannot be ignored. The extent to which reliance on knowledge-based representation will contribute to democratic decision-making is likely to depend on the resources needed to develop the types of knowledge relevant to representation work and on how these types of knowledge are determined.
PATIENT OR PUBLIC CONTRIBUTION: Patient representatives and practitioners in the field of patient engagement (including 13 interviewees, representatives of EUPATI and HTG developers) gave feedback on the interpretation of the findings during a multistakeholder workshop we organised. We also sent an interviewee an extended draft and discussed it during an online meeting. Claudia Egher presented these findings at a PEOF session in June 2023, which further contributed to their validation.

Keywords:  drug development; knowledge; knowledge‐based representation; participation; patient engagement; representation

DOI:  https://doi.org/10.1111/hex.13912
EMBO J. 2024 Aug 05.

Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.

Rodaria Roussou, Dirk Metzler, Francesco Padovani, Felix Thoma, Rebecca Schwarz, Boris Shraiman, Kurt M Schmoller, Christof Osman.

  Mitochondrial DNA (mtDNA) is present in multiple copies within cells and is required for mitochondrial ATP generation. Even within individual cells, mtDNA copies can differ in their sequence, a state known as heteroplasmy. The principles underlying dynamic changes in the degree of heteroplasmy remain incompletely understood, due to the inability to monitor this phenomenon in real time. Here, we employ mtDNA-based fluorescent markers, microfluidics, and automated cell tracking, to follow mtDNA variants in live heteroplasmic yeast populations at the single-cell level. This approach, in combination with direct mtDNA tracking and data-driven mathematical modeling reveals asymmetric partitioning of mtDNA copies during cell division, as well as limited mitochondrial fusion and fission frequencies, as critical driving forces for mtDNA variant segregation. Given that our approach also facilitates assessment of segregation between intact and mutant mtDNA, we anticipate that it will be instrumental in elucidating the mechanisms underlying the purifying selection of mtDNA.

Keywords:  Heteroplasmy; Mathematical Modeling; Mitochondria; Mitochondrial Fission; mtDNA

DOI:  https://doi.org/10.1038/s44318-024-00183-5