bims-curels 2025-03-23 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–03–23
ten papers selected by
Cure Mito Foundation

Small-molecule hypoxia therapy in mitochondrial disease.
Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis.
A rare de novo mutation, m.1630A>G, in the mitochondrial tRNAVal (MT-TV) gene in a child with epilepsy: case report and review of the literature.
Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
Using Human-Centred Design to Codesign Patient Engagement Tools With a Patient Advisory Council: Successes and Challenges.
Remarkable visual improvement in Leber hereditary optic neuropathy.
Developmental mitochondrial complex I activity determines lifespan.
Patient Perspectives: Patient as Teacher: The Impact of Listening to a Patient With Stiff-Person Syndrome on Her Disease Course.
Rare disease narratives on social media: A content analysis.
The role of mitochondria transfer in cancer biological behavior, the immune system and therapeutic resistance.

Cell. 2025 Mar 20. pii: S0092-8674(25)00207-7. [Epub ahead of print]188(6): 1462-1465

Small-molecule hypoxia therapy in mitochondrial disease.

Marni J Falk.

In this issue of Cell, Blume et al. provide compelling rationale for pursuing pharmacologic optimization of a small-molecule "HypoxyStat," which left-shifts the oxyhemoglobin dissociation curve in red blood cells in an attempt to induce an effective and sustained reduction of chronic tissue hyperoxia in primary mitochondrial disease (PMD) and was well-tolerated and effective for both pre-symptomatic and advanced disease treatment to extend survival and improve neurologic outcomes in a mouse model of Leigh syndrome spectrum.

DOI: https://doi.org/10.1016/j.cell.2025.02.019
Front Genet. 2025 ;16 1488956

Experiences from dual genome next-generation sequencing panel testing for mitochondrial disorders: a comprehensive molecular diagnosis.

Elizabeth Gorman, Hongzheng Dai, Yanming Feng, William James Craigen, David C Y Chen, Fan Xia, Linyan Meng, Pengfei Liu, Robert Rigobello, Arpita Neogi, Christine M Eng, Yue Wang.

   Introduction: The molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.
Methods: Dual genome panel testing by NGS was performed on a cohort of 1,509 unrelated affected individuals with suspected mitochondrial disorders. This test included 163 nuclear genes associated with mitochondrial diseases and the entire mitochondrial genome. A retrospective review was performed to evaluate diagnostic yield, disease-gene contributions, and heteroplasmy levels of pathogenic/likely pathogenic (P/LP) mitochondrial DNA (mtDNA) variants.
Results: The overall diagnostic yield was 14.6%, with 7.7% from the nuclear genome and 6.9% from the mtDNA genome. P/LP variants in nuclear genes were enriched in both well-established genes (e.g., POLG) and more recently described genes (e.g., FBXL4), highlighting the importance of keeping the panel design updated.
Conclusion: Variants in nuclear and mitochondrial genomes equally contributed to a 14.6% diagnostic yield in this patient cohort. Dual genome NGS testing provides a comprehensive framework for diagnosing mitochondrial disorders, offering clinical utility that can be considered as first-tier approach compared to single genome testing. Characterizing disease-causing genes, variants, and mtDNA heteroplasmy enhances understanding of mitochondrial disorders. Testing alternative tissues can further increase diagnostic yield.

Keywords:  NGS; dual-genome; functional group analysis; heteroplasmy; mitochondria

DOI:  https://doi.org/10.3389/fgene.2025.1488956
Transl Pediatr. 2025 Feb 28. 14(2): 367-372

A rare de novo mutation, m.1630A>G, in the mitochondrial tRNAVal (MT-TV) gene in a child with epilepsy: case report and review of the literature.

Qiong Wang, Yan Chen, Jun Li, Baomin Li.

   Background: Mitochondrial diseases represent a diverse group of disorders caused by defects in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), leading to a wide range of clinical manifestations. These diseases can affect multiple organs, particularly the nervous system, and present with symptoms such as epilepsy, neurodevelopmental delays, and muscular disorders. Over 300 genetic mutations have been linked to these conditions, with clinical heterogeneity being a hallmark of mitochondrial diseases. Early diagnosis and management are crucial, especially in pediatric cases where the disease burden may evolve with age. The aim of this study is to explore the variability in clinical presentation and progression associated with specific genetic mutations, using the case of a rare de novo mutation in the MT-TV gene as an illustrative example, and to discuss the implications for clinical diagnosis.
Case Description: This paper reports on a rare de novo mutation, m.1630A>G, in the MT-TV gene of a 3-year-old boy with epilepsy. In contrast to previously reported cases of the mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like disease/the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with the m.1630A>G mutation, this patient exhibited an earlier age of onset, simpler clinical manifestations, and lower heterogeneity levels in the blood.
Conclusions: This case offers significant insights into the intricate nature of mitochondrial diseases, especially in pediatric populations. It highlights the critical importance of regular physical examinations and vigilant monitoring for potential multi-system involvement, which are essential for early detection and timely symptomatic intervention to mitigate further damage. Furthermore, this case underscores the necessity to investigate factors influencing clinical penetrance, such as the interplay between mitochondrial and nuclear gene mutations, heterogeneity levels, and age-related accumulation of cellular damage, to better understand disease progression and optimize therapeutic strategies.

Keywords:  MT-TV; Mitochondrial disease; case report; m.1630A>G

DOI:  https://doi.org/10.21037/tp-24-462
Neurology. 2025 Apr;104(7): e213462

Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.

Sara Carli, Anna Levarlet, Daria Diodato, Enrico Silvio Bertini, Diego Martinelli, Alessandro Malandrini, Diego Lopergolo, Gian Nicola Gallus, Rebecca D Ganetzky, Chiara La Morgia, Valerio Carelli, Guido Primiano, Cristina Domínguez-González, Pablo Serrano-Lorenzo, Miguel A Martín, Anna Ardissone, Costanza Lamperti, Valeria Nicoletta, Thomas Klopstock, Felix Distelmaier, Leopold Zeng, Boriana Büchner, Michelangelo Mancuso, Markus Schuelke, Alessandro Prigione, Caterina Garone.

BACKGROUND AND OBJECTIVES: The mitochondrial DNA (mtDNA) genes MT-ATP6 and MT-ATP8 encode for subunits α and 8 (A6L) of the adenosine triphosphate synthase complex. Pathogenetic variants in MT-ATP6/8 cause incurable mitochondrial syndromes encompassing a wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI. Typically, higher levels of mtDNA variants lead to more severe symptomatology although even individuals with similar mtDNA mutational loads exhibit high clinical variability. Hence, the establishment of potential therapeutics is currently challenging. In this article, we present an international multicenter study designed to provide a retrospective natural history of patients with MT-ATP6/8 deficiency and to identify primary and secondary end points for future clinical trials.
METHODS: Clinical, biochemical, and molecular genetics data of patients with genetically confirmed MT-ATP6/8 defects were collected and analyzed from Italian, German, US, and Spain national reference centers through ethical committee-approved mitochondrial patients' national registries or local programs.
RESULTS: A cohort of 111 patients, 98 unreported, were analyzed (55 male, 56 female). Patients had infantile-onset disease (<1 year) in 44% of cases, pediatric-onset (≥1 year and ≤12 years) in 36%, and late-onset (>12 years) in 20%. Kaplan-Meier analysis showed a significant difference (p value = 0.0349) in the survival of infantile and pediatric patients compared with adult patients, although only 8% of patients were not alive at the last follow-up. The CNS was the most frequently affected tissue (93%), followed by the muscle (75%), eye (46%), and heart (18%). Brain MRI showed isolated Leigh-like lesions (58%), Leigh-like lesions and cortical and/or cerebellar atrophy (15%), isolated cerebellar atrophy (10%), and other lesions (21%). At the last follow-up, 11% of patients were wheelchair-bound. Metabolic acidosis or acute deterioration complicated the clinical course in ≅55% of early-onset patients. Molecular genetics studies identified 26 pathogenic variants (6 of them novel). Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers.
DISCUSSION: Our results define a more accurate classification based on the age at onset for MT-ATPase deficiency and provide fundamental clinical and biochemical data for disease management.

DOI: https://doi.org/10.1212/WNL.0000000000213462
Health Expect. 2025 Apr;28(2): e70230

Using Human-Centred Design to Codesign Patient Engagement Tools With a Patient Advisory Council: Successes and Challenges.

Madelyn Knaub, Santiago Leon, Surakshya Pokharel, Veronika Kiryanova, Kim Giroux, Prachi Khanna, Anna Rychtera, D'Arcy Duquette, Pamela Mathura, Nancy Verdin, Anshula Ambasta.

   BACKGROUND: Co-build is one of the four pillars of the Patient Engagement Framework from the Canadian Institutes of Health Research Strategy for Patient Oriented Research. Collaborating with Patient Research Partners (PRPs) using co-build approaches can enhance the applicability of healthcare tools produced. Human Centred Design (HCD), a problem-solving methodology focused on creating functional solutions for users, offers a promising approach to co-building patient engagement tools.
OBJECTIVE: To describe the process of using a HCD approach to co-build patient engagement tools with PRPs and to identify successes and challenges encountered.
METHODS: A HCD working group was formed from a Patient Advisory Council (PAC) that supports a research program to optimize laboratory test ordering in hospitalized patients. The HCD working group included nine PRPs, two patient engagement team members, and a HCD specialist. The working group employed the Double Diamond 4D design methodology: Discover, Define, Design, and Deliver, along with patient engagement principles of mutual respect, inclusiveness, support, and co-build. At the conclusion of the HCD process, we conducted a semi-structured debrief session to obtain perspectives on challenges and successes from all working group members. These were then summarized and collated iteratively with feedback from the group members.
RESULTS: The working group met 31 times in 12 months and co-developed three patient engagement tools (an infographic, a video, and a website) to educate and engage hospitalized patients about the bloodwork process. HCD working group members valued the diverse and inclusive environment within the group, the available enrichment opportunities in HCD and qualitative research, and presence of patient engagement team members. Challenges noted included delays in timelines due to difficulties with consensus-building and redundancy in discussion topics.
CONCLUSION: HCD approaches can be effectively combined with the principles of patient engagement to facilitate co-building with PRPs in healthcare. Future research is required to further the evidence for these strategies and their application in co-building processes, including use of clear project mapping and timelines and transparent consensus-building approaches.
PATIENT OR PUBLIC CONTRIBUTION: A PAC that consisted of nine PRPs guided this study. PRPs collaborated throughout the study. The current six PRPs were involved in the decision to write and are co-authors on this manuscript. PAC members had participated equally in the conduct of a prior qualitative study to understand patient needs about bloodwork processes in hospitals. With the guidance of a HCD specialist, PRPs contributed to decisions on content, wording, and imagery for the tools. The PAC members are currently collaborating on a study to implement these tools in hospitals and to evaluate the utility from a patient perspective.

Keywords:  codesign; human centred design; patient advisory council; patient engagement

DOI:  https://doi.org/10.1111/hex.70230
Jpn J Ophthalmol. 2025 Mar 17.

Remarkable visual improvement in Leber hereditary optic neuropathy.

Yasuyuki Takai, Akiko Yamagami, Mayumi Iwasa, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.

   PURPOSE: Leber hereditary optic neuropathy (LHON) typically has a poor visual outcome. In this study, we examined 8 cases of LHON that demonstrated remarkable visual improvement.
STUDY DESIGN: Retrospective observational study, clinical case series METHODS: We analyzed the clinical histories and outcomes of 8 patients (16 eyes) whose best corrected visual acuity (BCVA) improved to 0.7 or higher in at least 1 eye.
RESULTS: The median age of onset of the 7 male patients and 1 female patient was 17 years (range 8-58). Genetic testing revealed m.11778G>A mutations in 6 and m.14484T>C mutations in 2 of the patients. Of the 16 eyes, 15 improved to a BCVA of 0.7 or higher, whilst 1 eye achieved a final BCVA of 0.5. The lowest BCVA was below 0.1 in 12/16 eyes. BCVA improved to 0.1 or better within 1 year in 6/12 eyes and to 0.7 or better within 2 years in 12/15 eyes. In 10 eyes monitored by use of Humphrey Field Analysis (HFA; Fastpac, 30-2 program), the mean deviation improved from - 13.2 dB (- 23.6 to - 4.54) at its lowest to - 5.0 dB (- 15.6 to - 0.9) at the final measurement. Final HFA showed residual defects in the temporal region in 7/16 eyes. In the chronic phase, 10/12 eyes displayed either normal optic disc findings or partial temporal pallor.
CONCLUSION: In LHON cases with remarkable visual improvement, the recovery began earlier, and the visual field defects were relatively mild and tended to persist in the temporal region after improvement. Understanding these cases of notable improvement may inform future treatment strategies.

Keywords:  Humphry visual analyzer; Leber hereditary optic neuropathy; Papillomacular bundle; Visual recovery

DOI:  https://doi.org/10.1007/s10384-025-01185-4
EMBO Rep. 2025 Mar 17.

Developmental mitochondrial complex I activity determines lifespan.

Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.

  Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.

Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease

DOI:  https://doi.org/10.1038/s44319-025-00416-6
Neurology. 2025 Apr 22. 104(8): e213433

Patient Perspectives: Patient as Teacher: The Impact of Listening to a Patient With Stiff-Person Syndrome on Her Disease Course.

Aaron S Zelikovich, Barbara Zamorska, Nara Miriam Michaelson.

We highlight a memorable encounter with a patient who provided us with insight into her diagnosis of stiff-person syndrome (SPS) by helping us understand what it means to truly live with this rare disease. By actively imagining ourselves in a patient's position and trying to learn who they are as individuals, we can help them share their stories, empower them to participate in decisions, and determine their own definitions of successful outcomes. In our patient's case, she ultimately felt empowered to serve as a public advocate and spread greater awareness and deeper understanding of this rare disease. In this case-based narrative, we highlight key educational teaching points of SPS, including important symptoms, treatments, comorbidities, laboratory findings, and related electromyography results. We also compare the physician and patient perspectives to remind trainees to keep in mind the person behind every diagnosis. Small gestures of compassion such as creating space in clinic to listen to a patient's story can lead to stronger patient-physician therapeutic alliances and improved quality of life.

DOI: https://doi.org/10.1212/WNL.0000000000213433
Genet Med Open. 2025 ;3 102844

Rare disease narratives on social media: A content analysis.

Hannah J Park, Cassidy J Scott, Hadley Stevens Smith, Monica H Wojcik.

   Purpose: Social media provides an opportunity for the expression of people with rare conditions and may provide valuable insight into lived experiences to inform genomic care. Our objective was to describe the nature and content of rare disease video narratives on social media.
Methods: We reviewed content on a short-video-format social media website containing the tags of #raredisease, #raredisorder, or #raredisorders. Two authors independently coded videos for content matter and conducted thematic analysis using a mixed deductive-inductive approach. The demographic characteristics of the content and names of specific rare conditions were documented when available, as were the characteristics of the videos themselves.
Results: We reviewed 500 videos created by 299 unique users and identified 6 major themes: Spreading Awareness, Guidance for Others, Intimate View into Life, Interactions with Health care, Responses, and Requests for Support. The video narrators were typically family members or caregivers (50.2%) or the person affected (46.6%); a small percentage were health care professionals (2.2%). People with rare diseases in the video comprised both children (40.6%) and adults (52.6%). A total of 189 rare conditions were mentioned, the most common being Ehler-Danlos syndrome (7.8%), Sanfilippo syndrome (1.8%), and narcolepsy (1.8%).
Conclusion: Our data suggest that video-format social media allows community building among people affected by rare conditions. Insights from narratives expressed in this format may contribute to a better understanding of medical experiences in the context of daily life, both positive and negative, fostering empathy and leading to improvements in genomic medicine practice.

Keywords:  Genetics; Genomics; Narrative; Rare disease; Social media

DOI:  https://doi.org/10.1016/j.gimo.2025.102844
J Pharm Anal. 2025 Mar;15(3): 101141

The role of mitochondria transfer in cancer biological behavior, the immune system and therapeutic resistance.

Xintong Lyu, Yangyang Yu, Yuanjun Jiang, Zhiyuan Li, Qiao Qiao.

  Mitochondria play a crucial role as organelles, managing several physiological processes such as redox balance, cell metabolism, and energy synthesis. Initially, the assumption was that mitochondria primarily resided in the host cells and could exclusively transmit from oocytes to offspring by a mechanism known as vertical inheritance of mitochondria. Recent scholarly works, however, suggest that certain cell types transmit their mitochondria to other developmental cell types via a mechanism referred to as intercellular or horizontal mitochondrial transfer. This review details the process of which mitochondria are transferred across cells and explains the impact of mitochondrial transfer between cells on the efficacy and functionality of cancer cells in various cancer forms. Specifically, we review the role of mitochondria transfer in regulating cellular metabolism restoration, excess reactive oxygen species (ROS) generation, proliferation, invasion, metastasis, mitophagy activation, mitochondrial DNA (mtDNA) inheritance, immune system modulation and therapeutic resistance in cancer. Additionally, we highlight the possibility of using intercellular mitochondria transfer as a therapeutic approach to treat cancer and enhance the efficacy of cancer treatments.

Keywords:  Cancer biological behavior; Immune system; Mitochondria transfer; Therapeutic resistance

DOI:  https://doi.org/10.1016/j.jpha.2024.101141