bims-curels 2025-09-21 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–09–21
twelve papers selected by
Cure Mito Foundation

Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.
Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature.
Neuroimaging features of familial MT-TK related mitochondrial disease in a child.
Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.
[Clinical characteristics analysis of mitochondrial short-chain enoyl-CoA hydratase 1 deficiency with ECHS1 gene c.489G>A compound heterozygous variants].
Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.
Genetic background of neurological disorders with basal ganglia calcification.
Agency in action: Engaging patient participation in research.
Critical patient-oriented research: a fundamental shift in patient engagement.
Mitochondrial Transplantation: A Paradigm Shift in Osteoporosis Therapy.
Factors influencing online patient-reported ratings among shoulder surgeons.
Patient organisations, venture philanthropy and the ethics of pursuing cures over care.

MedComm (2020). 2025 Sep;6(9): e70385

Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.

Jialun Mei, Peng Ding, Chuan Gao, Jian Zhou, Zhiwei Li, Changqing Zhang, Junjie Gao.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins, culminating in defective oxidative phosphorylation and multisystem involvement. Key pathogenic mechanisms include heteroplasmy driven threshold effects, excess reactive oxygen species, disrupted mitochondrial dynamics and mitophagy, abnormal calcium signaling, and compromised mtDNA repair, which together cause tissue-specific energy failure in high demand organs. Recent advances have expanded the therapeutic landscape. Precision mitochondrial genome editing-using mitochondrial zinc finger nucleases, mitochondrial transcription activator-like effector nucleases, DddA-derived cytosine base editor, and other base editing tools-enables targeted correction or rebalancing of mutant genomes, while highlighting challenges of delivery and off-target effects. In parallel, metabolic modulators (e.g., coenzyme Q10, idebenone, EPI-743) aim to restore bioenergetics, and mitochondrial replacement technologies and transplantation are being explored. Despite these promising strategies, major challenges remain, including off-target effects, precise delivery, and ethical considerations. Addressing these issues through multidisciplinary research and clinical translation holds promise for transforming mitochondrial disease management and improving patient outcomes. By bridging the understanding of mitochondrial dysfunction with advanced therapeutic interventions, this review aims to shed light on effective solutions for managing these complex disorders.

Keywords:  base editing; gene therapy; genetic medicine; mitochondrial DNA (mtDNA); mitochondrial diseases; mitochondrial gene editing; therapeutic strategies

DOI:  https://doi.org/10.1002/mco2.70385
J Peripher Nerv Syst. 2025 Sep;30(3): e70060

Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature.

Daniele Mandia, Charline Benoit, Tanya Stojkovic, Yann Nadjar.

   BACKGROUND AND AIMS: TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cerebellar ataxia, neuropsychiatric symptoms, and characteristic brain MRI findings within the Leigh syndrome spectrum. Peripheral motor involvement has been described in a minority of cases but has rarely been documented with detailed neurophysiological data. We report a novel TTC19 variant in a patient presenting with a distinctive combination of central and peripheral motor involvement.
CASE REPORT: A male patient of Malian origin presented with cerebellar ataxia and attention deficits from early childhood. During adolescence, he developed additional features including dysarthria, dysphagia, dysexecutive syndrome, and signs of peripheral motor neuropathy. Brain MRI revealed T2-FLAIR hyperintensities in the basal ganglia and brainstem. Genetic testing identified a novel homozygous nonsense variant in TTC19 (c.235G>T, p.(Gly79*)). At age 19, he experienced two acute deteriorations associated with respiratory infections, leading to severe tetraparesis and diaphragmatic weakness. Neurophysiological studies confirmed a diffuse, axonal, pure distal motor neuropathy. Follow-up imaging showed progression and cavitation of brainstem lesions. The patient died from respiratory failure at age 20.
INTERPRETATION: This case, featuring a novel TTC19 variant and detailed electrophysiological data, further supports the presence of pure motor neuropathy within the phenotypic spectrum of TTC19-related disease. The co-occurrence of Leigh syndrome MRI findings and motor neuropathy represents a specific diagnostic clue that may help prioritize genetic testing in patients with overlapping central and peripheral motor involvement.

Keywords:  Leigh syndrome; TTC19; mitochondrial disease; motor neuropathy; respiratory chain complex III

DOI:  https://doi.org/10.1111/jns.70060
BMJ Case Rep. 2025 Sep 18. pii: e265230. [Epub ahead of print]18(9):

Neuroimaging features of familial MT-TK related mitochondrial disease in a child.

Leia Salongo, Ben Nguyen, John Ross Crawford.



Keywords:  Neuro genetics; Neuroimaging; Sleep disorders (neurology)

DOI:  https://doi.org/10.1136/bcr-2025-265230
QJM. 2025 Sep 18. pii: hcaf188. [Epub ahead of print]

Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.

Yuduo Wu, Xu Zhang, Zhengyang Zhang, Peng An, Yihua He, Hongjia Zhang, Yongting Luo, Junjie Luo.

  Marfan syndrome (MFS) is an autosomal genetic disease caused by FBN1 mutation. Patients with the same FBN1 mutation type exhibit different phenotypes, which indicates additional risk factors. Mitochondrial dysfunction was observed in the aorta of both MFS patients and Marfan murine models. Single nucleotide variants in mitochondrial DNA (mtDNA) may have harmful consequences on a cell. However, the association of mtDNA mutations with MFS has been unclear. Here, we used targeted mtDNA sequencing to detect whole blood mtDNA mutations from 48 healthy controls and 77 MFS patients, including 7 mother-offspring pedigrees. Three rare mtDNA mutations, m.279T > C, m.2361G > A, and m.3316G > A, were identified in a family whose predominant phenotype was eye lesions. The MFS patients with these mutations had more severe symptoms than family members without the mutation. m.9738G > A was identified in a family whose dominant phenotype was aortic manifestation. A sporadic case with this rare mutation site has an aortic aneurysm. We also described the mutation frequency and mutation rate in MFS. The frequency of all solid variants, nonsynonymous variants, pathogenic or likely pathogenic variants and variants of uncertain significance were more abundant in MFS patients compared to the control group. The mutation rate of the coding region, MT-rRNA and MT-tRNA were higher in the MFS group. These data demonstrate frequent mitochondrial mutation in MFS and suggest that the mtDNA mutation might be a potential modifier of MFS phenotypes.

Keywords:  Marfan syndrome; mitochondrial dysfunction; mtDNA sequencing; mtDNA variants

DOI:  https://doi.org/10.1093/qjmed/hcaf188
Zhonghua Er Ke Za Zhi. 2025 Sep 18. 63(10): 1085-1091

[Clinical characteristics analysis of mitochondrial short-chain enoyl-CoA hydratase 1 deficiency with ECHS1 gene c.489G>A compound heterozygous variants].

Y Liu, T Y Li, J L Wang, C L Xu, M H Song, M T Xu, Z M Liu, F Fang.

Objective: To summarize the clinical characteristics of children with mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) caused by c.489G>A (p.Pro163=) compound heterozygous variants in the ECHS1 gene, and to explore genotype-phenotype correlations. Methods: A case series study was performed to analyze clinical, biochemical, metabolic, imaging, genetic, treatment and follow-up outcomes of 24 children with ECHS1 gene c.489G>A(p.Pro163=) variant, who were diagnosed in the Department of Neurology, Beijing Children's Hospital from July 2010 to June 2024. Disease severity was assessed using the Newcastle Paediatric Mitochondrial Disease Scale, and Fisher exact test was applied to compare the improvement rate between valine-restricted and non-restricted groups. Results: These 24 children were all diagnosed after 2022, with a disease duration of 3.35 (1.25, 6.52) years at diagnosis. A total of 8 children initially had negative genetic results, and were finally confirmed by abnormal splicing of ECHS1 gene via skin fibroblast RNA sequencing, with the longest diagnostic time of 14 years. All 24 children presented with Leigh syndrome, including 11 boys and 13 girls, with an onset age of 1.46 (0.96, 2.79) years; 16 children (67%) were mild cases. Common initial symptoms included developmental delay (9 cases) and paroxysmal dystonia (9 cases), followed by developmental regression (3 cases), nystagmus (2 cases), and epilepsy (1 case). Main manifestations were dystonia (18 cases), developmental regression (14 cases), nystagmus (12 cases), developmental delay (11 cases), ataxia (10 cases), vision loss (9 cases), seizures (2 cases), and hearing impairment (1 case). Among 22 children who underwent blood and urine metabolic screening, 21 children (95%) had elevated urinary 2, 3-dihydroxy-2-methylbutyric acid and 19 children (86%) had elevated urinary S-(2-hydroxypropyl) cysteamine. All 24 children had symmetric abnormal signals in bilateral globus pallidus on cranial magnetic resonance imaging, 10 children had isolated globus pallidus involvement, and other common involved sites included caudate nucleus and brainstem (9 cases each), putamen (7 cases), and cerebral white matter (5 cases). At last follow-up, all 24 children survived, with a follow-up duration of 5.40 (2.75, 8.02) years and a maximum age of 17.8 years; 17 children (71%) had varying degrees of clinical improvement. There was no statistical difference in the improvement rate between children with or without valine-restricted diet (12/14 vs. 5/8,P=0309). A total of 18 pathogenic variants in the ECHS1 gene were identified among 24 children, 13 of which were distributed in exons 7 and 8; those carrying c.308T>C, c.523G>A, c.796A>G, and c.832G>A variants were mostly severe cases. Conclusions: Children carrying ECHS1 gene c.489G>A(p.Pro163=) compound heterozygous variants face significant diagnostic delay. Clinical awareness of this synonymous variant needs further improvement for timely diagnosis. All these cases present as Leigh syndrome, mostly mild, with no clear genotype-phenotype correlation identified.

DOI: https://doi.org/10.3760/cma.j.cn112140-20250718-00662
Curr Aging Sci. 2025 Sep 11.

Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.

Krishnaveni Manubolu, Raveesha Peeriga.

  Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.

Keywords:  Neurodegenerative diseases; artificial intelligence; biomarkers.; drug discovery; personalized medicine; pharmacy; precision medicine

DOI:  https://doi.org/10.2174/0118746098375978250820220024
J Neurol. 2025 Sep 14. 272(9): 632

Genetic background of neurological disorders with basal ganglia calcification.

Maha Yektay Farahmand, Joel Wallenius, Johan Wasselius, Olof Gråhamn, Andreas Puschmann, Andreea Ilinca.

   BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC.
METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history.
RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease.
CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.

Keywords:  Basal ganglia calcifications; Monogenic neurological disorders; Stroke; White matter hyperintensities; Whole genome sequencing

DOI:  https://doi.org/10.1007/s00415-025-13344-1
Patient Educ Couns. 2025 Sep 15. pii: S0738-3991(25)00720-7. [Epub ahead of print]141 109353

Agency in action: Engaging patient participation in research.

Jillianne Code, Heather Lannon, Aimee Lutrin.

   OBJECTIVES: To examine how patients with cardiovascular disease perceive and enact agency in research partnerships through decision-making, communication, health literacy, and sustained engagement.
METHODS: This qualitative study involved semi-structured interviews with 11 patient partners who participated in a national Masterclass on cardiovascular research. The Masterclass was designed to strengthen patient capacity for research involvement through education, mentorship, and collaborative activities. Interview transcripts were analyzed thematically, guided by the Patient Agency in Research (PAIR) framework, which conceptualizes agency as intentional, self-reflective action expressed through individual, proxy, and collective modes.
RESULTS: Participants reported increased confidence, research knowledge, and intentionality in their roles. They described navigating power imbalances, countering tokenism, and advocating for inclusive research cultures. Key findings included self-directed learning, empowerment, psychological safety, and the importance of trust and transparent communication.
CONCLUSION: Agency is a core element of meaningful patient engagement but must be deliberately cultivated through education, inclusive practices, and ongoing relational support.
PRACTICE IMPLICATIONS: Programs like the Masterclass can activate and strengthen patient agency, enabling individuals with lived experience to shape research in ways that are personally meaningful and scientifically impactful. By investing in patient capacity and fostering equitable research environments, institutions can move engagement beyond tokenism and toward partnerships that reshape the purpose-and the practice-of health research.

Keywords:  Cardiovascular research; Health literacy; Patient agency; Patient engagement; Qualitative study

DOI:  https://doi.org/10.1016/j.pec.2025.109353
CMAJ. 2025 Sep 14. 197(30): E960-E962

Critical patient-oriented research: a fundamental shift in patient engagement.

Ambreen Sayani, Alies Maybee.

DOI: https://doi.org/10.1503/cmaj.250603
Int J Nanomedicine. 2025 ;20 11169-11196

Mitochondrial Transplantation: A Paradigm Shift in Osteoporosis Therapy.

Jianlin Shen, Yue Lai, Qingping Peng, Xuan Lin, Shuxuan Chen, Liuqian Guo, Miao Xu, Yanjin Lu, Jiangqi Zhu, Xiaoning Lin, Cheng Zhang, Huan Liu.

  Osteoporosis, a global health crisis marked by compromised bone mineral density and heightened fracture susceptibility, demands innovative therapeutic strategies beyond conventional anti-resorptive approaches. Mitochondrial dysfunction, characterized by impaired bioenergetics, oxidative stress overload, and calcium dysregulation, has emerged as a central driver of osteoblast-osteoclast imbalance. Recent breakthroughs in mitochondrial transplantation (MT)-a revolutionary modality involving the transfer of functional mitochondria to metabolically compromised cells-have demonstrated unprecedented efficacy in preclinical osteoporosis models, restoring bone mass, microarchitecture, and mechanical strength. This review synthesizes cutting-edge insights into mitochondrial dynamics in bone homeostasis, dissects the molecular cascades linking mitochondrial failure to osteoporotic pathogenesis, and critically evaluates MT's potential to redefine osteoporosis management. We also discuss novel mechanisms of intercellular mitochondrial trafficking within the osteocyte dendritic network, explore bioengineered delivery platforms (eg, immunomodulatory hydrogels, nanoparticle-encapsulated mitochondria), and address emerging challenges in clinical translation, including donor source optimization, immune compatibility, and CRISPR-engineered mitochondrial genomes. By integrating single-cell omics data and AI-driven mitochondrial viability predictors, this work charts a roadmap for personalized mitochondrial medicine, positioning MT as a cornerstone of next-generation osteoporosis therapeutics.

Keywords:  mitochondrial disease; mitochondrial transfer; mitochondrial transplantation; osteoporosis

DOI:  https://doi.org/10.2147/IJN.S537166
JSES Int. 2025 Jul;9(4): 1371-1377

Factors influencing online patient-reported ratings among shoulder surgeons.

Krishna N Chopra, Sameer R Khawaja, Anna L Gorsky, Nicole L Greene, Frank L Vazquez, Joanne Y Zhou, Zaamin B Hussain, Michael B Gottschalk, Eric R Wagner.

   Background: Patient-reported ratings serve as a model of satisfaction and can play a major role in patient recruitment. Many variables can influence ratings on physician review websites (PRWs), such as social media use, academic productivity, fellowship type, and practice setting. This study examines such factors and their relationship with average ratings and overall patient engagement on PRWs.
Methods: The American Shoulder and Elbow Surgeons directory was queried for all active members who completed either a shoulder and elbow or sports medicine fellowship in the United States. Each name was searched online for professional accounts, and the number of followers was recorded for each. A summated social media presence score was calculated to identify the top 15% of social media users in each cohort. The presence of a practice group or personal website was also recorded, as was a surgeon's practice setting (academic vs. private) and region of practice. H-index was searched on Scopus. Average ratings, number of reviews, and number of comments were collected from Healthgrades, Google Reviews, and Vitals.
Results: A total of 231 shoulder surgeons were included in this review. Compared to shoulder surgeons in academic practice, those in private practice had higher mean ratings and patient engagement on PRWs. When comparing fellowships, shoulder and elbow fellowship-trained surgeons had a greater mean number of ratings on Google than those who completed a sports medicine fellowship. The top 15% of social media users had higher average patient ratings and engagement on Healthgrades compared to the rest of the cohort. There was a positive association between h-index and average rating on Google. No significant associations were found between patient satisfaction and the prestige of medical school or residency program.
Discussion: Several variables can influence patient satisfaction by way of average ratings and engagement on PRWs. Prospective patients are much more likely to select surgeons with higher ratings; thus, shoulder surgeons can use this information to capitalize on opportunities to improve patient retention, recruitment, and overall patient satisfaction.

Keywords:  Academic productivity; Fellowship; Online engagement; Patient ratings; Physician review websites; Shoulder and elbow; Social media; Sports medicine

DOI:  https://doi.org/10.1016/j.jseint.2025.04.011
J Med Ethics. 2025 Sep 16. pii: jme-2025-110875. [Epub ahead of print]

Patient organisations, venture philanthropy and the ethics of pursuing cures over care.

Matthew S McCoy.

  Patient organisations aim to advance the interests of patient populations living with various diseases, disabilities and health conditions. However, because the members of a given patient population often have varied or even conflicting interests, the way in which a patient organisation pursues its mission can be contentious, as it typically involves prioritising the interests of some patients over others. There is some evidence to suggest that in recent years, patient organisations have increasingly directed resources toward supporting research, a trend that may be spurred by the rise of venture philanthropy-an emerging model in which patient organisations make high-risk, high-reward research investments with the goal of advancing treatments and cures. While venture philanthropy has garnered significant support, it has also faced criticism from patients currently living with serious illnesses, who argue that research investments benefit future patients at the expense of services for current patients. Against the backdrop of these developments, this paper investigates the ethics of patient organisations pursuing cures over care. I begin by identifying a key assumption shared by proponents and critics of venture philanthropy, which suggests that patient organisations can permissibly choose whether they aim to benefit current or future patients. Yet I go on to argue that even if patient organisations may permissibly prioritise future patients, their promissory, stewardship and representative obligations may, under some circumstances, limit their discretion to invest in research. Under other circumstances, however, these same obligations may give patient organisations reasons to prioritise research.

Keywords:  Ethics- Medical; Health Care Economics and Organizations; Public Policy; Resource Allocation

DOI:  https://doi.org/10.1136/jme-2025-110875