bims-tyki2d 2025-12-14 papers

Issue of 2025–12–14
six papers selected by
Zoya Panahloo, UCB

Geroscience. 2025 Dec 12.

Elevated mtDNA copy number in older adults is linked to methylation of mitochondrial and nuclear regulatory regions.

Hongbo Chi, Hongying Shu, Yingmei Yang, Yuji Ikeno, Jiong Wu, Zhihong Wang, Habil Zare, Mikhail Alexeyev, Yidong Bai.

Growing evidence shows that epigenetic modification and mitochondrial dysfunction are hallmarks of aging and are associated with the development of a wide range of age-related diseases. Mitochondrial biogenesis, which is marked by mitochondrial DNA copy number (mtDNAcn), is one of the major regulations of mitochondrial function by a set of transacting elements, including mitochondrial DNA polymerase gamma (POLG), working on the mtDNA control region. In this study, we investigated the mtDNAcn and the methylation status at both mtDNA control and POLGA promoter regions in human blood cells from individuals with a wide range of ages. A total of 119 blood samples were collected, including 24 umbilical cord blood samples from newborns and 95 peripheral blood samples from individuals aged 18 to 96 years. We observed an increase in mtDNAcn, as well as a rise in the methylation levels of the mtDNA control region during aging, particularly in subjects aged ≥ 45. In addition, a positive correlation was also found between the methylation levels of the 4th CpG site in the POLGA promoter region and mtDNAcn during aging. These results suggest epigenetic regulation at mitochondrial and nuclear genes for mitochondrial biogenesis during aging in human blood cells.

Keywords: Aging; DNA methylation; DNA polymerase gamma A (POLGA); Mitochondrial DNA D-loop region; Mitochondrial DNA copy number; Mitochondrial biogenesis

DOI: https://doi.org/10.1007/s11357-025-02037-2

BMJ Case Rep. 2025 Dec 11. pii: e269373. [Epub ahead of print]18(12):

Juvenile/adult-onset POLG-related disease unmasked by valproate-associated fulminant hepatic failure.

Akshay Mathavan, Kanika Rathi, Lalitkumar J Mundhra, Akash Mathavan.

DNA polymerase subunit gamma-1 (POLG)-related disease is a heterogeneous spectrum of mitochondrial disorders with neurologic and hepatic manifestations. We report a woman in her 20s who developed refractory seizures followed by fulminant hepatic failure after valproic acid exposure. Laboratory evaluation revealed low copper indices without evidence of Wilson disease, neuroimaging demonstrated evolving posterior-predominant abnormalities, and liver biopsy showed acute hepatitis with microvesicular change and 'two-toned' hepatocytes. Rapid whole-genome sequencing identified compound-heterozygous POLG variants c.1399G>A p.(Ala467Thr) and c.2243G>C p.(Trp748Ser), confirming a juvenile/adult-onset POLG-related disorder. This case highlights key diagnostic pitfalls, including potential misdirection of copper studies and risk of valproate hepatotoxicity in patients with unrecognised POLG variants. Supportive clues like occipital-predominant electroencephalogram/MRI changes, rapid neurologic-hepatic progression and hepatic microvesicular pathology can aid early suspicion but are not universally present. Prompt genetic testing and multidisciplinary follow-up are essential to guide management, avoid harmful therapies and anticipate the trajectory of this multisystem disease.

Keywords: Epilepsy and seizures; Genetics; Immunology; Liver disease

DOI: https://doi.org/10.1136/bcr-2025-269373

J Med Genet. 2025 Dec 11. pii: jmg-2025-111137. [Epub ahead of print]

Challenges associated with disclosing results from whole genome sequencing to diagnose paediatric rare diseases: analysis of parent-clinician interactions.

Holly Ellard, Jhumana Ali, Phoebe Buxton, Myra Bluebond-Langner, Celine Lewis.

BACKGROUND: Whole genome sequencing (WGS) has recently been introduced as a diagnostic test for patients with particular rare diseases in the National Health Service (NHS) in England. Little is known about the process of communicating results from WGS to families in practice.
METHODS: We audio-recorded clinicians and parents discussing the results of WGS for their child's rare disease diagnosis as part of a larger mixed-methods evaluation of the implementation of the NHS Genomic Medicine Service during its early years.
RESULTS: 10 consultations were audio-recorded across four NHS Trusts. Clinical indications for WGS were related to neurological and developmental disorders. Seven parents received a genetic diagnosis for their child's condition, two received a variant of uncertain significance, and one received a no primary finding result. One parent also received an incidental finding for their child. Challenges in discussing results included (1) explaining a diagnosis when the genotype was established before detailed phenotyping, (2) navigating follow-up for an adult-onset condition identified in childhood, (3) disclosing an unexpected diagnosis for a parent from trio testing and (4) conveying a diagnosis with an uncertain prognosis.
CONCLUSION: This study illustrates some of the issues that can arise from unexpected and uncertain information when returning results from broad-scope genomic testing for paediatric neurological and developmental disorders. Further study of actual interactions between clinicians and families discussing results from WGS across different specialities and conditions is needed to inform guidance on communication of results within this rapidly evolving area of medicine.

Keywords: Child Health; Genetic Counseling; Genetics, Medical; Genomics; Health Services Research

DOI: https://doi.org/10.1136/jmg-2025-111137

J Genet Couns. 2025 Dec;34(6): e70154

Genetic testing as moral technology: Navigating legitimacy, uncertainty, and access in rare disease diagnosis.

Nicolás Schöngut-Grollmus, Dolores Steverlynck, Gabriela Repetto.

Genetic testing is often portrayed as a neutral tool for clinical clarification. However, in the context of rare diseases, it plays a far more complex role in the moral, bureaucratic, and social experiences of patients and families. Drawing on qualitative research conducted in Chile, this article explores how genetic testing is not only a diagnostic resource but also a symbolic and institutional technology that shapes how care, legitimacy, and identity are negotiated across multiple domains. We analyze 11 narrative interviews with patients and family members affected by rare diseases, alongside 10 interviews with healthcare professionals, including geneticists and clinicians, and two hybrid forums. Using a grounded, interdisciplinary approach informed by Science and Technology Studies (STS) and medical sociology, we identify four key themes: (1) the moral resolution offered by diagnosis after long periods of uncertainty; (2) structural barriers to accessing testing, including social capital and institutional discretion; (3) the epistemic ambiguity of genetic information, especially in cases of inconclusive results; and (4) the mobilization of diagnoses beyond the clinic, including in education, legal systems, and reproductive decisions. Our findings suggest that genetic testing functions as a moral and classificatory technology: it produces recognition, redistributes responsibility, and serves as a resource for navigating fragmented care systems. For genetic counselors, this research offers insights into how patients and families interpret, act on, and negotiate the consequences of genetic information. Understanding the broader moral and institutional landscape in which testing occurs can enhance counseling practices, particularly in under-resourced or structurally unequal contexts. This study contributes to growing efforts to embed genetic counseling in a wider social and ethical framework. By attending to how genetic testing is lived, contested, and deployed, we highlight the need for a counseling practice that is attuned to both genomic data and the realities of care.

Keywords: epistemic justice; genetic testing; health equity; patient experience; rare diseases

DOI: https://doi.org/10.1002/jgc4.70154

Orphanet J Rare Dis. 2025 Dec 09.

Transition from childhood to adulthood in neuromuscular disorders: results from the ERN EURO-NMD survey.

Teresinha Evangelista, Houda Ali, Charlotte Handberg, Thomas Sejersen, Ros Quinlivan, Isabella Moroni, Marion Masingue, Susana Quijano-Roy, Antonio Atalaia, Ulrike Schara-Schmidt, Kristl G Claeys.

BACKGROUND: Neuromuscular diseases (NMDs) are rare, progressive conditions that require lifelong, multidisciplinary care. Advances in diagnosis and treatment have increased survival into adulthood, making the transition from paediatric to adult care a critical stage of its management. However, evidence suggests that transition practices remain inconsistent across Europe. This study aimed to map and evaluate the current transition practices for patients with NMDs across Europe.
METHODS: A cross-sectional survey was conducted by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) to assess current transition practices across European healthcare providers (HCPs). Sixty-seven healthcare professionals from 20 countries participated. The survey explored training provision, transition structures, professional involvement, timing, psychosocial support, and perceived barriers. Both descriptive and thematic analyses were performed.
RESULTS: Only 29.9% of respondents reported structured transition protocols, and fewer than one in five (17,9%) had received formal training in transition care. The age to initiate transition was reported for most centres at 17-18 years, even though most clinicians identified 15-16 years as the ideal starting point. Multidisciplinary collaboration was present in some centres but was inconsistently implemented. Barriers included insufficient staff, lack of funding, inadequate adult care services, and poor inter-team communication. Post-transfer feedback to paediatric teams was limited. Despite these challenges, 59.7% of respondents believed that ERN EURO-NMD could facilitate improvement in transition care.
CONCLUSIONS: Transition care for patients with NMDs in Europe remains fragmented and under-resourced. To ensure continuity and improve outcomes, structured, multidisciplinary transition models are needed. A European roadmap, coordinated by ERN EURO-NMD, could harmonise practices, support professional training, and guide policy development across member states.

Keywords: Adult neurology; Care coordinator; Continuity of care; ERN EURO-NMD; Healthcare policy; Neuromuscular diseases; Paediatric neurology; Paediatric to adult care; Rare diseases; Transition of care; Transition programmes

DOI: https://doi.org/10.1186/s13023-025-04144-x