bims-curels 2025-02-23 papers

Issue of 2025–02–23
seventeen papers selected by
Cure Mito Foundation

Mitochondrion. 2025 Feb 14. pii: S1567-7249(25)00007-8. [Epub ahead of print]81 102010

Endurance swimming exacerbates mitochondrial myopathy in mice with high mtDNA deletions.

Sho Hanada, Kaori Ishikawa, Takanaga Shirai, Tohru Takemasa, Kazuto Nakada.

Recent studies have reported that endurance exercise enhances mitochondrial function, facilitating discussions of its potential as a therapeutic strategy for mitochondrial diseases caused by the accumulation of mutant mitochondrial DNA (mtDNA). In this study, we assessed the effects of endurance exercise on muscle pathology in a mitochondrial disease mouse model (mito-miceΔ) that is characterized by severe clinical phenotypes owing to the predominant accumulation of mtDNA with a large-scale deletion (ΔmtDNA). Contrary to expectations that endurance exercise may enhance mitochondrial function, endurance exercise exacerbated muscle pathology in mito-miceΔ. Therefore, exercise interventions should be potentially avoided in patients with severe mitochondrial diseases.

Keywords: Endurance exercise; Mitochondrial diseases; Mitochondrial respiratory function; Mouse model; Muscle atrophy

DOI: https://doi.org/10.1016/j.mito.2025.102010

Med Genet. 2025 Apr;37(1): 57-63

Leber's hereditary optic neuropathy - current status of idebenone and gene replacement therapies.

Thomas Klopstock, Leopold H Zeng, Claudia Priglinger.

Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease, and was the first to be linked to mitochondrial DNA (mtDNA) variations. Recently, autosomal recessive forms of LHON were described in addition to the classical mtDNA-associated forms. Clinically, LHON manifests with subacute and painless loss of central visual acuity, in most cases starting unilaterally, and involving the second eye a few weeks later. Almost all LHON cases are caused by pathogenic variants in genes that code for proteins relevant for function of Complex I of the respiratory chain. The Complex I dysfunction in LHON leads to decreased ATP synthesis and to increased production of reactive oxygen species which ultimately initiates dysfunction and apoptosis of retinal ganglion cells and their axons, the optic nerve. Idebenone, a synthetic CoQ derivative, is a potent intramitochondrial antioxidant and can shuttle electrons directly to complex III of the respiratory chain, thereby bypassing complex I deficiency. On the basis of several clinical trials, it has been approved as a treatment for LHON in 2015 (in the EU). In addition, direct intravitreal gene replacement therapy is being investigated, with several late-stage clinical trials already completed. In the future, gene editing of mtDNA variants may also become a therapeutic option.

Keywords: Complex I; LHON; gene therapy; idebenone; mtDNA

DOI: https://doi.org/10.1515/medgen-2024-2066

Neurology. 2024 Apr 09. 102(7_supplement_1): 6306

Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017).

Emanuele Barca, Adam Kroopnick, Alexander Houck, Kiran Thakur, Rachelle Dugue, Zarazuela Zolkipli-Cunningham, Marni Falk, Amy Goldstein, Matthew Demczko, Ralitza Gavrilova, Austin Larson, Johan Van Hove, Russell Saneto, Richard Buchsbaum, John Thompson, Michio Hirano.

OBJECTIVE: This analysis of Adult-Onset Leigh Syndrome (LS) patients from the North American Mitochondrial Disease Consortium (NAMDC) Registry aims to enhance clinical insights, improve diagnoses, and uncover potential modifiers.
BACKGROUND: LS is a rare syndrome linked to defects in more than one hundred genes. Most LS patients develop subacute neurological deterioration or regression before age two years. The pathological and radiological hallmarks are the subacute necrotizing degeneration of basal ganglia, cerebellum, brainstem, and/or cervical spinal cord, frequently triggered by metabolic stress. A small group of patients develop central nervous system involvement later in life.
DESIGN/METHODS: This retrospective study stemmed from a case of a twenty-five-year-old man with mild developmental delay and sensory-motor neuropathy admitted for worsening weakness. During his hospital stay, he developed a rapidly progressive encephalopathy and classic LS radiological findings. Intrigued by this observation, we interrogated the NAMDC registry to retrieve data from other adult-onset LS individuals. The registry contains demographic, manifestation, genetic, imaging, and biochemistry data from more than 2100 subjects enrolled from 17 centers in North America and Canada.
RESULTS: We identified six subjects with onset of CNS manifestations after age 18. Most of the subjects had been involved of other organ systems preceding the CNS lesions. Four probands had pathogenic variants in nuclear-encoded mitochondria metabolism genes, one in mitochondrial DNA-encoded ATP synthase subunit gene, and one patient remained genetically undefined. The disease progression varied among the cohort, with probands harboring nuclear variants experiencing a slower course compared to the individual with a mitochondrial DNA defect, who suffered a rapid, progressive, and fatal deterioration.
CONCLUSIONS: Our data show that mitochondrial patients with LS experience evolving and progressive phenotypes, and the presence of manifestations in other organs often precedes LS in adults, suggesting that clinicians should carefully avoid metabolic stressors known to precipitate neurodegeneration in subjects with the observed genetic variants. Disclosure: Dr. Barca has nothing to disclose. Dr. Kroopnick has nothing to disclose. Dr. Houck has nothing to disclose. Dr. Thakur has received personal compensation for serving as an employee of World Health Organization. Dr. Thakur has received personal compensation for serving as an employee of Pan American Health Organization. Dr. Thakur has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Delve Bio. The institution of Dr. Thakur has received research support from Center for Disease Control and Prevention. The institution of Dr. Thakur has received research support from National Institute of Health. Dr. Dugue has nothing to disclose. Dr. Zolkipli-Cunningham has nothing to disclose. An immediate family member of Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lumiere. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mission Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Primera Therapeutics. Marni Falk has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Imel Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MiMo Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GenoMind. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casma Therapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mayflower, Inc.. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Biosciences. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Foresite Labs. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stealth BioTherapeutics. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha Gene Therapies. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Larimar Therapeutics. Marni Falk has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Khondrion. Marni Falk has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for United MItochondrial Disease Foundation. Marni Falk has stock in Rarefy Therapeutics. Marni Falk has stock in RiboNova Inc. The institution of Marni Falk has received research support from Merck. The institution of Marni Falk has received research support from Saol Therapeutics. The institution of Marni Falk has received research support from Stealth Biotherapeutics. The institution of Marni Falk has received research support from Astellas. The institution of Marni Falk has received research support from UMDF. The institution of Marni Falk has received research support from CureARS Foundation. The institution of Marni Falk has received research support from Mission Therapeutics. The institution of Marni Falk has received research support from Cyclerion. The institution of Marni Falk has received research support from NIH. The institution of Marni Falk has received research support from DOD. The institution of Marni Falk has received research support from FDA. Marni Falk has received intellectual property interests from a discovery or technology relating to health care. Marni Falk has received publishing royalties from a publication relating to health care. Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reneo Pharmaceuticals . Dr. Demczko has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Manuals. Dr. Gavrilova has nothing to disclose. Austin Larson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Illumina. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. An immediate family member of Austin Larson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for Tisento. Austin Larson has received personal compensation in the range of $0-$499 for serving as a Consultant for UCB. The institution of Austin Larson has received research support from Stealth Biotherapeutics. The institution of Austin Larson has received research support from Astellas. The institution of Austin Larson has received research support from Entrada. The institution of Austin Larson has received research support from Neuren. The institution of an immediate family member of Austin Larson has received research support from Neurocrine. Johan Van Hove has received intellectual property interests from a discovery or technology relating to health care. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for REATA. Dr. Saneto has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Pharmaceuticals. The institution of Dr. Saneto has received research support from NIH. The institution of Dr. Saneto has received research support from Zogenix. The institution of Dr. Saneto has received research support from GW Pharmaceuticals. The institution of Dr. Thompson has received research support from NIH. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Modis Therapeutics (a subsidiary of Zogenix). Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epirium Bio. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Innovation Specialist. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Platform Q Health. The institution of Dr. Hirano has received research support from Modis Therapeutics (a subsidiary of Zogenix). The institution of Dr. Hirano has received research support from Cyclerion. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of $0-$499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.

DOI: https://doi.org/10.1212/WNL.0000000000206383

BMC Med Res Methodol. 2025 Feb 15. 25(1): 39

Patient partner engagement in the publication process: challenges and possible solutions.

Krista E Cooksey, Mark Neuman, Mara Bollini, Bethany Pennington, Hugo de O Campos, Kathleen Oberst, Melissa Wurst, Mary C Politi.

Patient engagement in research is gaining traction as an international standard, and often requirement, of many health research funding agencies. Drivers of this increase include patient interest, increased attention to and recognition of the value of patients' voices in research, and more patients leading or partnering in the conduct research. Patient engagement includes collaborating and providing insights into research question and study design, and may extend to the publication process. When patients contribute to publications, they can bring unique perspectives that may enhance the impact, reach, and utility of the research in real-world contexts. Currently, there is limited systematic guidance to support patient partners as they navigate this complex publication process. As a result, it can be difficult for patient partners to understand when and how they should be included as authors, how to collaborate in the writing process, and how to complete mandatory tasks during the submission process. In this paper, we review barriers and facilitators within existing publication practices and offer recommendations to ensure that the scientific publication process is more transparent and accessible for patient partners.

Keywords: Co-authorship; Co-production; Collaboration; Patient engagement; Patient partnership

DOI: https://doi.org/10.1186/s12874-025-02495-4

Case Rep Ophthalmol. 2024 Jan-Dec;15(1):15(1): 852-858

Leber Hereditary Optic Neuropathy "Plus" with the m.14487 T>C Mutation as the Causality of Hemidystonia: A Case Report.

Fumio Takano, Kaori Ueda, Norio Chihara, Mina Arai, Mari Sakamoto, Takuji Kurimoto, Yuko Yamada-Nakanishi, Makoto Nakamura.

Introduction: Leber hereditary optic neuropathy (LHON) complicated with extraocular symptoms is called LHON plus. We describe a case of LHON plus with a rare mutation, which also caused dystonia.
Case Presentation: An 18-year-old male patient developed symptoms of dystonia at the age of 15 years. Two years later, he noticed decreased visual acuity and central scotoma in the left eye. One month later, the same symptoms occurred in the right eye. Although the optic discs in both eyes revealed mildly redness and edematous change, no abnormal findings were detected on fluorescence fundus angiography and orbital magnetic resonance imaging. Mitochondrial deoxyribonucleic acid (mtDNA) sequencing detected the m.14487 T>C mutation. From clinical course and fundus findings, the case was diagnosed LHON. The optic nerve gradually atrophied and central scotoma remained.
Conclusion: The m.14487 T>C mutation is one of the causative mutations in patients with dystonia or Leigh encephalopathy and a minor mutation in patients with LHON. However, in the present case, ocular symptoms were more severe than systematic symptoms and the disease course was consistent with LHON. For the above reasons, this case can be diagnosed as LHON plus. Whole mtDNA sequencing is important in diagnosing LHON if none of the three major mutations are detected.

Keywords: Dystonia; Leber hereditary optic neuropathy plus; Rare mitochondrial point mutation

DOI: https://doi.org/10.1159/000542202

BioTech (Basel). 2025 Feb 12. pii: 9. [Epub ahead of print]14(1):

Bioinformatics Tools for NGS-Based Identification of Single Nucleotide Variants and Large-Scale Rearrangements in Mitochondrial DNA.

Marco Barresi, Giulia Dal Santo, Rossella Izzo, Andrea Zauli, Eleonora Lamantea, Leonardo Caporali, Daniele Ghezzi, Andrea Legati.

The unique features of mitochondrial DNA (mtDNA), including its circular and multicopy nature, the possible coexistence of wild-type and mutant molecules (i.e., heteroplasmy) and the presence of nuclear mitochondrial DNA segments (NUMTs), make the diagnosis of mtDNA diseases particularly challenging. The extensive deployment of next-generation sequencing (NGS) technologies has significantly advanced the diagnosis of mtDNA-related diseases. However, the vast amounts and diverse types of sequencing data complicate the interpretation of these variants. From sequence alignment to variant calling, NGS-based mtDNA sequencing requires specialized bioinformatics tools, adapted for the mitochondrial genome. This study presents the use of new bioinformatics approaches, optimized for short- and long-read sequencing data, to enhance the accuracy of mtDNA analysis in diagnostics. Two recent and emerging free bioinformatics tools, Mitopore and MitoSAlt, were evaluated on patients previously diagnosed with single nucleotide variants or large-scale deletions. Analyses were performed in Linux-based environments and web servers implemented in Python, Perl, Java, and R. The results indicated that each tool demonstrated high sensitivity and specific accuracy in identifying and quantifying various types of pathogenic variants. The study suggests that the integrated and parallel use of these tools offers a significant advantage over traditional methods in interpreting mtDNA genetic variants, reducing the computational demands, and provides an accurate diagnostic solution.

Keywords: NGS; bioinformatics; mitochondrial DNA; mtDNA

DOI: https://doi.org/10.3390/biotech14010009

Free Radic Biol Med. 2025 Feb 13. pii: S0891-5849(25)00087-5. [Epub ahead of print]

Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.

Juan Wang, Rongjuan Zhao, Jing Ma, Jiangbo Qin, Huiqiu Zhang, Junhong Guo, Xueli Chang, Wei Zhang.

Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.

Keywords: FDXR; ataxia; ferroptosis; idebenone; mitochondrial diseases

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.02.012

Cell. 2025 Feb 12. pii: S0092-8674(25)00098-4. [Epub ahead of print]

HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.

Skyler Y Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D Midha, Brandon T L Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H Jain.

We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.

Keywords: Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy

DOI: https://doi.org/10.1016/j.cell.2025.01.029

J Neuromuscul Dis. 2024 Dec 08. 22143602241296276

Privacy-by-Design with Federated Learning will drive future Rare Disease Research.

Simon Süwer, Md Shihab Ullah, Niklas Probul, Andreas Maier, Jan Baumbach.

Up to 6% of the global population is estimated to be affected by one of about 10,000 distinct rare diseases (RDs). RDs are, to this day, often not understood, and thus, patients are heavily underserved. Most RD studies are chronically underfunded, and research faces inherent difficulties in analyzing scarce data. Furthermore, the creation and analysis of representative datasets are often constrained by stringent data protection regulations, such as the EU General Data Protection Regulation. This review examines the potential of federated learning (FL) as a privacy-by-design approach to training machine learning on distributed datasets while ensuring data privacy by maintaining the local patient data and only sharing model parameters, which is particularly beneficial in the context of sensitive data that cannot be collected in a centralized manner. FL enhances model accuracy by leveraging diverse datasets without compromising data privacy. This is particularly relevant in rare diseases, where heterogeneity and small sample sizes impede the development of robust models. FL further has the potential to enable the discovery of novel biomarkers, enhance patient stratification, and facilitate the development of personalized treatment plans. This review illustrates how FL can facilitate large-scale, cross-institutional collaboration, thereby enabling the development of more accurate and generalizable models for improved diagnosis and treatment of rare diseases. However, challenges such as non-independently distributed data and significant computational and bandwidth requirements still need to be addressed. Future research must focus on applying FL technology for rare disease datasets while exploring standardized protocols for cross-border collaborations that can ultimately pave the way for a new era of privacy-preserving and distributed data-driven rare disease research.

Keywords: artificial intelligence; data protection; federated learning; personalized medicine; rare diseases

DOI: https://doi.org/10.1177/22143602241296276

Zhongguo Dang Dai Er Ke Za Zhi. 2025 Feb 15. pii: 1008-8830(2025)02-0205-07. [Epub ahead of print]27(2): 205-211

[Combined oxidative phosphorylation deficiency type 7 caused by C12orf65 gene mutations: a case report and literature review].

Xiao-Yi Chen, Yong-Jie Zhu, Jie Deng, Yan-Li Ma, Jun-Fang Suo, Yuan Wang, Yuan-Ning Ma.

OBJECTIVES: To investigate the clinical features and gene mutation characteristics of combined oxidative phosphorylation deficiency type 7 (COXPD7) caused by mutations in the C12orf65 gene, and to enhance the awareness of this disease.
METHODS: A child diagnosed with COXPD7 in the Department of Neurology, Children's Hospital Affiliated to Zhengzhou University in 2021 was included, along with 10 patients reported in the literature. All subjects were analyzed for their genotypes and clinical phenotypes.
RESULTS: A total of 11 patients with COXPD7 were included, comprising 1 reported in this study and 10 from the literature. Among the 11 patients, 9 had homozygous mutations in the C12orf65 gene, while 2 had compound heterozygous mutations, which were identified as frameshift or nonsense mutations. The age of onset ranged from 1 day to 2 years, and clinical manifestations included optic nerve atrophy and delays in intellectual and motor development. Eight patients exhibited external ophthalmoplegia, and five patients displayed spastic paralysis. Cranial magnetic resonance imaging revealed optic nerve atrophy in all 11 patients, abnormal brainstem signals in 10 patients, and a lactate peak on brainstem magnetic resonance spectroscopy scans in 3 patients.
CONCLUSIONS: COXPD7 associated with the C12orf65 gene results from homozygous or compound heterozygous mutations, with primary clinical manifestations of optic nerve atrophy and delays in intellectual and motor development. Some patients may also present with spastic paralysis or external ophthalmoplegia. Cranial imaging reveals symmetrical abnormal signals in bilateral basal ganglia and brainstem, and a lactate peak is observed on brainstem magnetic resonance spectroscopy scans.

Keywords: C12orf65 gene; Child; Combined oxidative phosphorylation deficiency type 7; Leigh syndrome; Mitochondrial disease

DOI: https://doi.org/10.7499/j.issn.1008-8830.2409063

Mo Med. 2025 Jan-Feb;122(1):122(1): 53-59

From Serendipity to Scalability in Rare Disease Patient Collaborations.

Kerry Grens, Judith L Weisenberg, Robin C Ryther, Harrison W Gabel.

As the rate of diagnosis for rare disease increases, so does the need to develop scalable solutions to address patient community needs. Drawing upon our experiences in rare intellectual and developmental disability research, advocacy, and treatment, we present two examples of how collaboration between patient groups, clinicians, and investigators at Washington University in St. Louis have generated invaluable resources to accelerate toward treatments. These successful partnerships serve as models for building research and clinical infrastructure for rare diseases.

Orphanet J Rare Dis. 2025 Feb 14. 20(1): 74

Real-world evidence for Pompe disease remains fragmented. Comment on "A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem" by Klein et al.

Michelle E Kruijshaar, Tiffany House, Benedikt Schoser, Pascal Laforêt, Maudy T M Theunissen, Stephan Wenninger, Thomas Hundsberger, Jordi Diaz-Manera, Ans T van der Ploeg, Nadine A M E van der Beek.

In a recent publication by Klein et al., the need for real-world data on rare diseases is highlighted. We strongly support this need, and the collaboration with the patient community to collect data, as promoted in this publication. Our concern, however, is that this paper may be misunderstood as suggesting that the Sanofi-run Rare Disease Registries (RDRs) are sufficient to provide the datasets needed to evaluate current and future therapies. Industry-driven registries focus on their own product(s) and, therefore, do not provide the opportunity to compare products from different companies. Today, multiple companies produce treatments for all diseases included in the RDRs. Each company will have to run its own registry for regulatory purposes. This will lead to data fragmentation, which is prohibitive of truly understanding the effects of the various treatment options for these rare diseases. Therefore, independently funded and owned registries are essential to generate real-world evidence (RWE) unrelated to specific products. We discuss options for this for Pompe disease, including the International Pompe Survey, which has collected patient-reported outcomes independently from industry since 2002. This letter aims to raise awareness of the problem of siloed data and advocate for a new way forward where independent registries provide post-marketing surveillance data.

Keywords: Patient-reported outcomes; Pompe disease; Rare disease registries; Real-world evidence

DOI: https://doi.org/10.1186/s13023-025-03552-3

J Eval Clin Pract. 2025 Feb;31(1): e70010

Capturing Real-World Rare Disease Patient Journeys: Are Current Methodologies Sufficient for Informed Healthcare Decisions?

Kristen A Cribbs, Lucas T A Blackmore, Asia R Banks, Da Sol Kim, Betsy J Lahue.

RATIONALE: Despite growing emphasis among healthcare decision-makers on patient perspectives and real-world outcomes to inform care and access decisions, understanding of patient journey experiences in rare diseases remains limited due to data collection and evaluation challenges.
AIMS AND OBJECTIVES: This systematic literature review (SLR) assessed study designs, methodologies, and outcomes reported in real-world investigations of rare disease patient journeys.
METHODS: Searches in PubMed and Google Scholar targeted English-language publications and congress proceedings from 1 January 2014, to 30 April 2024, including rare disease patients, caregivers, or healthcare providers. Keywords included 'Journey', 'Path', or 'Odyssey'. Two reviewers independently assessed eligibility and abstracted data. Descriptive analyses and quality assessments were conducted.
RESULTS: Thirty-one studies met inclusion criteria, with 296,548 participants spanning over 600 rare diseases. Most studies used prospective observational (61%) and cross-sectional (26%) designs and were conducted in Europe (45%). Interviews (39%) and surveys (29%) were common methodologies. Patients (87%) were the primary research focus, compared to caregivers (32%) or providers (10%). The most studied journey stages were 'Pre-diagnosis/Screening' (97%) and 'Diagnosis' (84%), while 'Disease Awareness' (16%) and 'Treatment Adherence' (6%) were less common. Across 164 outcomes reported, frequent outcomes included 'Healthcare Resource Utilization' (94%), 'Symptoms' (74%), and 'Time-to-Diagnosis' (71%). Fewer studies reported 'Costs' (19%), 'Caregiver/Family Burden' (16%), and 'Productivity' (13%). Time-to-diagnosis averaged 11.8 years and a median of 6.1 years. All but one study (97%) was rated low or very low quality due to observational designs.
CONCLUSION: Most rare disease patient journey evidence focuses on 'Pre-diagnosis/Screening' and 'Diagnosis' stages using qualitative methods and surveys. While symptoms, time-to-diagnosis, and resource utilization were commonly reported, evidence gaps included treatment adherence, caregiver burden and productivity. Longitudinal assessments to collect real-world care and treatment burden outcomes, including caregiver perspectives, can enhance both clinician and policy decision-making for individuals living with rare diseases.

Keywords: methods; patient outcome assessment; rare diseases; systematic review

DOI: https://doi.org/10.1111/jep.70010

Brain Commun. 2025 ;7(1): fcae453

Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment.

Biallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.170G > A) and three ultra-rare or novel predicted loss-of-function biallelic variants. Updated clinical-radiological data from previously reported families and a literature review compiling clinical features of all reported patients with isolated complex I deficiency caused by 43 genes encoding complex I subunits and assembly factors are also provided. Our cohort (mean age 7.8 ± 5.4 years; range 2.5-18) predominantly presented a moderate-to-severe neurodevelopmental syndrome with oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and epilepsy (46%). Neuroimaging revealed bilateral symmetric T2 hyperintense substantia nigra lesions (91.6%) and optic nerve atrophy (66.6%). Protein modeling suggests missense variants destabilize a critical junction between the hydrophilic and membrane arms of complex I. Fibroblasts from two patients showed reduced complex I activity and compensatory complex IV activity increase. This study characterizes NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13-related disease in 13 individuals, highlighting genotype-phenotype correlations.

Keywords: Leigh syndrome; NDUFA13; complex I deficiency; mitochondrial disorders; neurodevelopmental disorder

DOI: https://doi.org/10.1093/braincomms/fcae453

HGG Adv. 2025 Feb 17. pii: S2666-2477(25)00021-1. [Epub ahead of print] 100418

Polyamine Metabolism is Dysregulated in COXFA4 Related Mitochondrial Disease.

Jonathan Marquez, Stephen Viviano, Erika Beckman, Jenny Thies, Joshua Friedland-Little, Christina T Lam, Engin Deniz, Emily Shelkowitz.

Most of the chemical energy that organisms rely on to support cellular function is generated through oxidative phosphorylation, a metabolic pathway in which electron donors, NADH and FADH, are oxidized through a series of successive steps to generate adenosine triphosphate. These redox reactions are orchestrated by a series of five protein complexes that sit within the mitochondrial membrane. Deficiency of cytochrome c oxidase, the fourth of these complexes, is a recognized cause of mitochondrial disease. COXFA4, encodes one of the protein subunits of cytochrome c oxidase and variants in COXFA4 have recently been reported in individuals with a range of symptoms. These can include feeding difficulties, poor growth, cardiomyopathy, Leigh or Leigh-like disease, and neurodevelopmental delay. Though these symptoms vary widely between individuals. Yet, a mechanistic understanding of the connection between COXFA4 loss and these varied disease manifestations is lacking. Using animal modeling in Xenopus, we explored the ramifications of coxfa4 loss of function on the early developing heart. We then conducted a hypothesis naive analysis of cellular gene expression in the context of COXFA4 deletion and discovered a downstream deficiency in the ornithine decarboxylase pathway. Small molecule-based modulation of the ornithine decarboxylase pathway in our model modified the extent of disease including improvement of cardiac function. Our findings point to a mechanism by which COXFA4 dysfunction leads to tissue specific disease.

DOI: https://doi.org/10.1016/j.xhgg.2025.100418

Rev Infirm. 2025 Feb;pii: S1293-8505(24)00380-4. [Epub ahead of print]74(308): 31

[The role of the patient partner].

Rozenn Morel.

DOI: https://doi.org/10.1016/j.revinf.2024.12.030