bims-curels 2025-07-27 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–07–27
nine papers selected by
Cure Mito Foundation

Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.
Implications of mtDNA in human health and diseases.
NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.
Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.
[A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G].
Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.
Transforming Objective Participatory Patient Advocacy.
From insight to impact: a qualitative study on pharmaceutical industry professionals' perceptions of the value of patient engagement.
Editorial - Patient perspectives on new therapies for genetic diseases.

Cureus. 2025 Jun;17(6): e86670

Mutation of NDUFAF2 Linked to Mitochondrial Complex I Deficiency.

Anwar R Alhamad, Aziza Mushiba, Huda Alkhawaja, AbdullabAli PeerZada, Shahad Bawazeer, Mohammed Saleh.

  Mitochondrial complex I deficiency is an autosomal recessive disorder caused by homozygous mutations in the reduced form of nicotinamide adenine dinucleotide (NADH). It is characterized by a wide range of signs and symptoms that affect numerous human systems and organs. This disease causes neurological issues, including encephalopathy, recurrent epilepsy, intellectual disability, ataxia, and involuntary movements. The initial step of the mitochondrial respiratory chain, during which protons are transported across the inner mitochondrial membrane along with electron transfer from NADH to ubiquinone, is catalyzed by NADH: ubiquinone oxidoreductase. In this case report, we describe a patient presenting with severe, rapidly progressive neurological loss who harbored a novel mutation in NDUFAF2 identified using exome sequencing. At six months of age, her mother noticed delayed motor development. Thereafter, the patient developed metabolic acidosis and abnormal movements, mimicking seizures triggered by aspiration pneumonia, with elevated serum lactate levels. Genetic testing revealed a c.127G>A mutation in NDUFAF2, consistent with mitochondrial complex I deficiency. This case highlights the utility of exome sequencing as a powerful and cost-effective tool for diagnosing clinically heterogeneous disorders such as mitochondrial diseases. Mitochondrial complex I deficiency is an important differential diagnosis in patients with recurrent central hypoventilation. Our findings expand the mutational spectrum of this rare disease.

Keywords:  case report; episodic respiratory failure; mitochondrial complex i deficiency; ndufaf2; recurrent encephalopathy

DOI:  https://doi.org/10.7759/cureus.86670
BioTechnologia (Pozn). 2025 ;106(2): 209-222

Implications of mtDNA in human health and diseases.

Smruthi Seethashankar, Shruti Hariharan, Venkatachalam Deepa Parvathi.

  The maternally inherited autonomous organelles, mitochondria, are responsible for a myriad of functions within the cell. They may contain more than one copy of DNA and can themselves be present in multiple numbers within a cell. The integrity of the mitochondrial genome is affected by variations in DNA copy number or the presence of mutations. Compromising this integrity has been documented to result in disorders affecting various systems. Focusing on such trends could enhance knowledge essential for developing strategies to manage these disorders. Irregular patterns of mitochondrial DNA (mtDNA) copy number (CN) variation have been identified in various cancers. Reduced mtDNA CN has been associated with neurodegenerative disorders, cardiovascular diseases, and kidney disorders. Mutations in the mitochondrial respiratory chain complex have been linked to cardiomyopathy. High rates of mtDNA deletions have been found in aging patients and subjects with Parkinson's disease. While sperm function appears to deteriorate with increased mtDNA CN, oogenesis involves a significant increase to enable the oocyte to achieve fertilization and further development. Prospective therapies to treat mitochondrial diseases may include approaches that aim to reduce the levels of mutant mtDNA below the disease-causing threshold, such as targeted removal of defective mitochondria. Mutations in mitochondrial DNA contribute to various diseases; some single substitutions appear to disrupt the normalcy of more than one organ, underscoring the importance of mitochondrial genome integrity. The presence of mutations and copy number variations may serve as diagnostic markers and also provide insight into prognosis.

Keywords:  cancer; cardiovascular diseases; fertility; mitochondrial diseases; mtDNA; mtDNA CN; neurodegenerative diseases; renal diseases

DOI:  https://doi.org/10.5114/bta/204532
BMJ Case Rep. 2025 Jul 18. pii: e266155. [Epub ahead of print]18(7):

NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency.

Parul Mittal, Samendra Karkhur, Vidhya Verma, Priti Singh.

  Mutations in the NDUFV1 gene, encoding a subunit of mitochondrial complex I, are typically associated with severe neurological disorders such as Leigh syndrome. We report a pre-teen girl with progressive bilateral optic atrophy and steady visual deterioration, without neurological findings or systemic involvement. Neuroimaging was unremarkable for white matter lesions or structural brain lesions. Whole-exome sequencing demonstrated a homozygous missense mutation (c.1156C>T, p. Arg386Cys) in NDUFV1, implying a nuclear-encoded complex I defect. Laboratory analysis revealed increased lactate levels, consistent with mitochondrial dysfunction. Despite treatment with coenzyme Q, riboflavin and idebenone, no significant visual improvement occurred. This case represents a novel phenotype of NDUFV1-associated disease isolated optic atrophy without systemic involvement expanding the clinical spectrum of NDUFV1 mutations. Recognising this unique mitochondrial optic neuropathy may aid early diagnosis and targeted management.

Keywords:  Genetics; Neuroimaging; Neuroopthalmology; Retina; Visual pathway

DOI:  https://doi.org/10.1136/bcr-2025-266155
J Hum Genet. 2025 Jul 22.

Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction.

Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Taku Omata, Maki Nodera, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Holger Prokisch, Hiroshi Matsumoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki.

Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.

DOI: https://doi.org/10.1038/s10038-025-01356-8
Rinsho Shinkeigaku. 2025 Jul 24.

[A case of a spinal cord involvement in an adult mitochondrial disease with an m.3243A>G].

Ken-Ichi Shibata, Tatsuya Mukai, Hideaki Nakagaki, Sukehisa Nagano.

  A 44-year-old woman had weakness in her right lower limb, a right Babinski reflex, paresthesia in her left lower leg, hypoesthesia at and below the T6 dermatome, and abnormality of the vibrational perception in both legs after prolonged exertion. Her medical history comprised sensorineural hearing loss and diabetes. Furthermore, her child had mitochondrial disease with an m.3243A>G. The patient was diagnosed with maternally inherited diabetes and deafness (MIDD), and the disease-causing variant was identified as m.3243A>G. Cerebrospinal fluid analysis revealed the presence of oligoclonal bands. T2-weighted magnetic resonance imaging showed hyperintensity of the right side of the spinal cord at the level of the 4th thoracic vertebra. This paper examines spinal cord lesions that occur in patients with mitochondrial diseases.

Keywords:  Spinal cord; m.3243A>G; maternally inherited diabetes and deafness (MIDD); mitochondrial disease

DOI:  https://doi.org/10.5692/clinicalneurol.cn-002071
N Engl J Med. 2025 Jul 16.

Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease.

Robert McFarland, Louise A Hyslop, Catherine Feeney, Rekha N Pillai, Emma L Blakely, Eilis Moody, Matthew Prior, Anita Devlin, Robert W Taylor, Mary Herbert, Meenakshi Choudhary, Jane A Stewart, Douglass M Turnbull.

Pathogenic variants in mitochondrial DNA (mtDNA) are a common cause of severe, often fatal, inherited metabolic disease. A reproductive care pathway was implemented to provide women carrying pathogenic mtDNA variants with reproductive options. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (and thus receipt of a mitochondrial donation), and there have been 8 live births. All 8 children were healthy at birth, with no or low levels of mtDNA heteroplasmy in blood. Hyperlipidemia and cardiac arrhythmia developed in a child whose mother had hyperlipidemia during pregnancy; both of the child's conditions responded to treatment. Infant myoclonic epilepsy developed in another child, with spontaneous remission. At the time of this report, all the children have made normal developmental progress. (Funded by the U.K. National Health Service and others.).

DOI: https://doi.org/10.1056/NEJMoa2503658
Ther Innov Regul Sci. 2025 Jul 21.

Transforming Objective Participatory Patient Advocacy.

Pat Furlong, Timothy R Franson, Peter J Pitts.

  Objective Participatory Patient Advocacy (OPPA) is an important evolution from traditional patient advocacy to a strategic, data-driven approach that significantly impacts the patient voice vis-a-vis both drug development and the regulatory processes, particularly within the realm of rare diseases. Focusing on the exemplar of Parent Project Muscular Dystrophy (PPMD) and its work in Duchenne muscular dystrophy (DMD), this article highlights how OPPA leverages scientific rigor, collaborative partnerships, and a patient-centered perspective to accelerate the development and approval of effective therapies. The era of anecdote-driven advocacy is waning, making way for a new paradigm where patient advocacy organizations act as pivotal stakeholders in the drug development ecosystem. OPPA is characterized by its use of data-driven tools such as surveys, preference studies, and real-world evidence to inform research priorities, clinical trial designs, and regulatory decision-making. By adopting this objective approach, patient advocacy groups can contribute valuable insights into patient needs, preferences, and risk tolerance, which can then be integrated into the drug development process to ensure that therapies are both effective and aligned with patient values. These initiatives encompass a wide range of activities, including investing in cutting-edge research, advocating for legislative support for intramural research, and fostering collaborative partnerships with researchers, industry stakeholders, and regulatory agencies. PPMD's efforts to identify and validate biomarkers, map proteins, and develop industry guidance demonstrate its commitment to building a solid scientific foundation for DMD drug development. A key focus of the article is the collaborative effort between the FDA, PPMD, care-givers, healthcare providers, scientists, and regulatory experts to and the FDA, culminating in the creation of patient-initiated draft guidance for industry developing DMD therapies. This achievement signifies a shift in the regulatory landscape, with the FDA recognizing patient perspectives that has led to more flexible and patient-centered regulatory pathways and the approval of promising new therapies. Objective Participatory Patient Advocacy calls for continued collaboration between advocacy groups, regulators, industry, and researchers. These partnerships are essential to sustaining progress and ensuring meaningful outcomes. The lessons learned from PPMD's experience offer a roadmap for other rare disease communities to emulate, paving the way for a future where patient voices are central to the development of innovative therapies and the improvement of patient care.

Keywords:  Biomarkers; Drug development; Duchenne’s muscular dystrophy; Exondys 51; FDA guidances; Patient voice; Patient-reported outcomes; Protein mapping; Quality of life data; Real world evidence; Risk/benefit analysis

DOI:  https://doi.org/10.1007/s43441-025-00841-8
Curr Med Res Opin. 2025 Jul 23. 1-20

From insight to impact: a qualitative study on pharmaceutical industry professionals' perceptions of the value of patient engagement.

Fatima I Auwal, Elizabeth J Clark, Caroline S Copeland, Graham R McClelland.

   INTRODUCTION: Patient engagement (PE) is increasingly recognised as a critical component of clinical research and pharmaceutical development. However, its implementation remains inconsistent, and evidence of its impact limited.
OBJECTIVES: This study explored pharmaceutical professionals' perspectives on the value, challenges, and facilitators of PE in medicine development.
METHODS: Twenty-eight industry professionals from Europe and North America were interviewed online (November 2023-May 2024). Data were analysed using inductive reflexive thematic analysis.
RESULTS: The result showed that while PE is acknowledged for its potential in enhancing trial design, patient recruitment and retention, enhancing data quality, regulatory success and market access-the evidence demonstrating its impact in these areas are still limited. Key challenges highlighted were the lack of standardised ways for assessing PE's value, limited access to patient organisations in some regions, and disparities in regulatory requirements that complicate global adoption. Additionally, practical barriers-such as time, resource constraints, and cultural differences, hinder the implementation of consistent and meaningful engagement practices. The study also identified a number of potential enablers for creating systematic and consistent PE: the use of digital tools, cost-effective engagement methods, culturally sensitive communication approaches, partnerships with patient advocacy groups and the establishment of PE as a recognised scientific discipline.
CONCLUSION: This research emphasised the need for robust methodologies and standardised PE practices to demonstrate return on engagement and its contribution to successful development of innovative medicines.

Keywords:  benefits; challenges; impact; medicine development; patient engagement; pharmaceutical industry; value

DOI:  https://doi.org/10.1080/03007995.2025.2537888
Med Genet. 2025 Jul;37(3): 163-167

Editorial - Patient perspectives on new therapies for genetic diseases.

Miriam Elbracht, Christiane Zweier, Ilona Krey-Grauert.

DOI: https://doi.org/10.1515/medgen-2025-2018