bims-curels Biomed News
on Leigh syndrome
Issue of 2025–09–07
fifteen papers selected by
Cure Mito Foundation
  1. Retinal multimodal-imaging and functional tests in a mitochondrial disease with focal and segmental glomerulosclerosis.
  2. Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
  3. Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
  4. Addressing global regulatory challenges in rare disease drug development.
  5. Emerging Approaches in Data-Driven Drug Discovery for Rare Diseases.
  6. Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
  7. Expert recommendations on sharing medical information with patients: a qualitative study.
  8. Advancements in Nonviral Gene Editing Strategies for Rare Diseases.
  9. Exploring Patient and Caregiver Perceptions of the Facilitators and Barriers to Patient Engagement in Research: A Participatory Qualitative Study.
  10. Pervasive non-random mitochondrial DNA heteroplasmy in the hybrid water frog Pelophylax esculentus.
  11. Advances in Cell and Gene Therapy for Rare Disease Treatment.
  12. Hospital Patient and Family Advisory Council Accelerators and Barriers: A Qualitative Study.
  13. From Broad Consent to Patient Engagement: A Framework for Consent Management and Study Oversight.
  14. MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
  15. Prenatal diagnosis of rare genetic disorders: fourteen years' experience of a tertiary genetic centre from India.
  1. Int J Ophthalmol. 2025 ;18(9): 1770-1776
    Retinal multimodal-imaging and functional tests in a mitochondrial disease with focal and segmental glomerulosclerosis.
    Xiao-Hong Liu, Xi Shen, Yi-Sheng Zhong.
      The phenotypes of the adenine-to-guanine transition at position 3243 of mitochondrial DNA (m.3243A>G) are highly variable, with different symptoms observed in different patients. These include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); maternally inherited diabetes and deafness syndrome (MIDD); other syndromic conditions; or non-syndromic mitochondrial disorders. Renal involvement associated with this mutation generally manifests as subnephrotic proteinuria, progressive deterioration of kidney function, and increased morbidity. The retinopathies linked to the m.3243A>G mutation have heterogeneous presentations, characterized by variable degrees of retinal pigment epithelium (RPE) atrophy and hyperpigmentation at the posterior pole. As a severe phenotype of the m.3243A>G mutation, MELAS combined with focal and segmental glomerulosclerosis (FSGS) is rare. We herein firstly reported in detail the ophthalmic manifestations of a patient with this condition. Additionally, we reviewed the literature on fundus, ophthalmic electrophysiology, and optical coherence tomography (OCT) findings related to the m.3243A>G mutation.
    Keywords:  MELAS; m.3243A>G; mitochondrial retinopathy; multimodal imaging; ophthalmic electrophysiology; optical coherence tomography
    DOI:  https://doi.org/10.18240/ijo.2025.09.19
  2. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101554
    Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
    Qinglan Ling, Matthew Rioux, Harrison Higgs, Yuhui Hu, Scarlett E Dwyer, Steven J Gray.
      Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for SURF1-related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for SURF1-related Leigh syndrome, warranting further translational studies.
    Keywords:  AAV; Leigh syndrome; SURF1; adeno-associated virus; gene replacement therapy; gene therapy; mitochondrial diseases; overexpression toxicity
    DOI:  https://doi.org/10.1016/j.omtm.2025.101554
  3. Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102678
    Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.
    Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee.
      Mitochondrial DNA (mtDNA) base editors are powerful tools for investigating mitochondrial diseases. However, their editing efficiency can vary significantly depending on the target site within the mtDNA. In this study, we developed two improved versions of the mitochondrial adenine base editor (Hifi-sTALED and αnHifi-sTALED) by modifying components other than the TadA8e-V28R deaminase variant. These enhancements significantly increased editing efficiency while preserving minimal off-target effects across the transcriptome. Using these optimized editors, we achieved improved mtDNA editing in mouse embryos and successfully generated mt-Rnr1 mutant mice with high heteroplasmic loads. Functional analyses revealed that the mt-Rnr1 mutation impaired mitochondrial function, as indicated by reduced ATP production and decreased oxygen consumption rate (OCR). These findings demonstrate the utility of the enhanced base editors in generating mitochondrial disease models and advancing research in mitochondrial genetics.
    Keywords:  MT: RNA/DNA Editing; TALED; base editing; mitochondria; mitochondrial editing; mtDNA
    DOI:  https://doi.org/10.1016/j.omtn.2025.102678
  4. Drug Discov Today. 2025 Aug 30. pii: S1359-6446(25)00175-8. [Epub ahead of print] 104462
    Addressing global regulatory challenges in rare disease drug development.
    Enrico Costa, Vijayalekshmi Ajith, Ahmed F Al Khaldi, Antonella Isgrò, Kerry J Lee, Riccardo Luigetti, Anna M G Pasmooij, Violeta Stoyanova-Beninska, Eveline Trachsel, Julienne Vaillancourt, Steffen Thirstrup.
      Despite progress in rare disease treatment, many conditions still lack therapeutic options. In addition to specific legislation promoting research and investment, regulators have supported early dialogs with stakeholders, optimized processes and expedited the approval of medicines in areas with unmet medical needs, such as rare diseases. However, several challenges persist, particularly in generating robust evidence. The introduced flexibility must be balanced with uncertainty management. Our analysis identifies several priorities: establishing a common global regulatory language; recognizing and validating surrogate endpoints; involving patients in defining meaningful outcomes; and leveraging digital health technologies and decentralized clinical trials. These tools offer opportunities to improve evidence generation and access, supporting more efficient and inclusive development processes where traditional approaches can be limited or unfeasible.
    Keywords:  Rare diseases; expedited pathways; medicines regulation; orphan drugs; unmet medical needs
    DOI:  https://doi.org/10.1016/j.drudis.2025.104462
  5. Curr Drug Metab. 2025 Aug 25.
    Emerging Approaches in Data-Driven Drug Discovery for Rare Diseases.
    Mohamed Abbas, Muneer Parayangat, Mohammad Alaa Hussain Al-Hamami, Hashim Elshafie, Mohamad Yahya H Al-Shamri, R Resmi.
      Rare diseases present unique challenges in drug discovery and development, primarily due to small patient populations, limited clinical data, and significant variability in disease mechanisms. The primary objective of this review is to examine the integration of pharmacokinetics (PK) and drug metabolism data into data-driven drug discovery approaches, particularly in the context of rare diseases. By incorporating advanced computational techniques such as Machine Learning (ML) and Artificial Intelligence (AI), researchers can better predict PK parameters, optimize drug candidates, and identify personalized therapeutic strategies. AI integration with genomic and proteomic data reveals previously unidentifiable pathways, fostering collaboration among researchers, clinicians, and pharmaceutical companies. This interdisciplinary approach reduces development timelines and costs while enhancing the precision and effectiveness of therapies for patients with rare diseases. This review highlights the critical role of absorption, distribution, metabolism, and excretion (ADME) in understanding drug behavior in genetically diverse populations, thereby enabling the development of tailored treatments for patients with rare diseases. Additionally, it evaluates the opportunities and limitations of integrating PK/PD (pharmacodynamics) models with multi-omics data to improve drug discovery efficiency. Key examples of enzyme-drug interactions, metabolic pathway analysis, and AIbased PK simulations are discussed to illustrate advancements in predictive accuracy and drug safety. This review concludes by emphasizing the transformative potential of integrating PK and metabolism studies into the broader framework of data-driven drug discovery, ultimately accelerating therapeutic innovation and addressing unmet medical needs in rare diseases.
    Keywords:  Rare diseases; artificial intelligence; computational drug discovery; digital twin models; high-throughput screening; machine learning; personalized medicine.
    DOI:  https://doi.org/10.2174/0113892002383220250729100138
  6. Int J Toxicol. 2025 Aug 28. 10915818251369414
    Mitochondria: Key Mediator for Environmental Toxicant-Induced Neurodegeneration.
    Nishi Shah, Bhagawati Saxena, Richa Gupta.
      Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.
    Keywords:  environmental toxicants; heavy metals; mitochondrial dysfunction; neurodegenerative disorders; pesticides
    DOI:  https://doi.org/10.1177/10915818251369414
  7. BMC Health Serv Res. 2025 Aug 28. 25(1): 1137
    Expert recommendations on sharing medical information with patients: a qualitative study.
    Herman Egenberg, Hanne Cathrine Lie, Jennifer Gerwing, Julia Menichetti.
       BACKGROUND: Sharing medical information with patients is essential for patient-centered care, yet empirical research to guide information sharing in clinical practice is inconsistent and scattered across disciplines. Clinicians rarely use established models for sharing information, and patients inconsistently understand and remember the information shared.
    OBJECTIVE: Explore experts' views on the task of sharing information.
    DESIGN: Qualitative study using semi-structured interviews and reflexive thematic analysis.
    PARTICIPANTS: We recruited fifteen expert clinical communication teachers from six countries, using the snowball method.
    APPROACH: Interviews were recorded, transcribed, and analysed by authors with both clinical, teaching and research experience, using reflexive thematic analysis.
    RESULTS: We conceived four themes addressing the task of sharing information. The overarching theme was: (1) Sharing information with patients should be a dialogue, not a lecture. Further, to improve how they share information with patients, clinicians might want to: (2) Help the patient process emotions; (3) Explore the patient's knowledge and perspective; (4) Tailor and structure the information. Each theme included common challenges and solutions for clinicians.
    CONCLUSIONS: The findings align with and expand current models for communicating with patients. The themes integrate knowledge from different disciplines, such as psychology, medicine and communication science. The findings provide support for the role of information sharing in patient-centered care and shared decision making. The findings can guide clinicians in the task of sharing information with patients and shape curriculum and training development.
    Keywords:  Clinical communication; Expert interviews; Health literacy; Medical information
    DOI:  https://doi.org/10.1186/s12913-025-13223-5
  8. Hum Gene Ther. 2025 Sep 01.
    Advancements in Nonviral Gene Editing Strategies for Rare Diseases.
    Jimena Pérez-Maroto, Laura Sepp-Lorenzino, Diego Castaño-Esteban, Daniela Palacios, Begoña Sot.
      Rare diseases are serious and often chronic conditions that affect a small number of individuals. However, with over 7,000 rare diseases identified, their cumulative global numbers and impact are substantial. A considerable proportion of these conditions is caused by genetic abnormalities. Among these, monogenic disorders are of particular relevance, as they are caused by mutations in specific genes. The development of gene therapy, and more specifically, gene editing, offers innovative approaches to treat these rare diseases. A significant challenge associated with the implementation of such strategies concerns the delivery of gene editing tools. Nonviral vectors based on nanomaterials have demonstrated considerable potential as promising alternatives to viral vectors, thereby overcoming their disadvantages. The biocompatibility and tunability of nanoparticles, along with their potential capacity to target diverse tissues, positions them as a promising therapeutic approach for the treatment of a wide range of organ-specific rare diseases. Here, we review current progress in the development and evaluation of novel nanomedicine strategies for gene editing in rare diseases, highlighting new gene editing approaches, delivery systems, and potential targets.
    Keywords:  CRISPR-Cas9; gene editing; nanoparticles; nonviral vectors; rare diseases
    DOI:  https://doi.org/10.1177/10430342251372056
  9. J Particip Med. 2025 Sep 02.
    Exploring Patient and Caregiver Perceptions of the Facilitators and Barriers to Patient Engagement in Research: A Participatory Qualitative Study.
    Sasha Melanda Kullman, Louise Bird, Amy Clark, Amanda Doherty-Kirby, Diana Ermel, Nathalie Kinnard, Marion Knutson, Andrew Milroy, Lesley Singer, Anna Maria Chudyk.
       BACKGROUND: Patient engagement in research is the meaningful and active involvement of patient/caregiver partners (i.e., patients and their family/friends) in research priority-setting, conduct, and governance. With the proper support, patient/caregiver partners can inform every stage of the research cycle, but common barriers often prevent their full engagement.
    OBJECTIVE: This participatory qualitative study answered the question: What are the facilitators and barriers to patient engagement experienced by patient/caregiver partners in a Canadian research context?
    METHODS: Participants were N = 13 patient/caregiver partners (Mage = 62 years, 85% women; 100% White) from four provinces who completed 60-90-minute semi-structured online interviews. The interviews were transcribed verbatim. One researcher and one patient/caregiver partner reviewed the transcripts and curated a dataset of 90 participant quotations representing facilitators and barriers to patient engagement. This dataset was co-analyzed using Participatory Theme Elicitation alongside seven patient/caregiver partners with diverse identities who were not among the participants we interviewed and, therefore, contributed novel perspectives.
    RESULTS: Four themes depicted factors that facilitate meaningful patient engagement alongside barriers that arise when these factors are not in place: (1) Co-defining roles and expectations, (2) Demonstrating the value and impact of engagement, (3) Psychological safety, and (4) Educating the public, patient/caregiver partners, and researchers. We then discuss how barriers to enacting these four factors can be mitigated and provide a practical checklist of considerations for both researchers and patient/caregiver partners for engaging together throughout the research cycle.
    CONCLUSIONS: Researchers and patient/caregiver partners should draw from our findings to mitigate engagement barriers and facilitate meaningful engagement experiences.
    DOI:  https://doi.org/10.2196/79538
  10. BMC Ecol Evol. 2025 Sep 02. 25(1): 91
    Pervasive non-random mitochondrial DNA heteroplasmy in the hybrid water frog Pelophylax esculentus.
    Jelena Radojicic, Jon Bent Kristoffersen, Eirini-Slavka Polovina, Pavlos Pavlidis, Emmanuel D Ladoukakis.
       BACKGROUND: Heteroplasmy, the presence of more than one type of mitochondrial DNA (mtDNA) within an individual, is an exception to the maternal transmission of mtDNA and has been observed in several animal species. A central question is whether heteroplasmy among individuals and across generations is mainly influenced by genetic drift or by selection.
    RESULTS: We quantified heteroplasmy in eight males, eight females and eight unfertilized eggs per female from a natural population of the hybrid frog species Pelophylax esculentus (between P. ridibundus and P. lessonae). After excluding sequencing error and potential sources of contamination, we found that all individuals and most of the eggs were heteroplasmic, containing 2-5 different haplotypes, from which one was very common and the rest appeared at very low frequencies (at maximum 2%). We observed a single lessonae haplotype, which was present in females and in their eggs but absent from all males. On the other hand, we observed four different ridibundus haplotypes that were present in males, females and eggs. Eggs had significantly lower heteroplasmy levels than their mothers.
    CONCLUSIONS: The distribution of haplotypes between males and females, the difference of heteroplasmy levels between mothers and their eggs, and results from simulations suggest that drift alone is not sufficient to explain the observed patterns of heteroplasmy.
    Keywords:  Bottleneck; Frogs; Heteroplasmy; Hybrids; Mitochondrial DNA; Pelophylax; Selection
    DOI:  https://doi.org/10.1186/s12862-025-02436-1
  11. Int J Stem Cells. 2025 Sep 01.
    Advances in Cell and Gene Therapy for Rare Disease Treatment.
    Hyun Jin Baek, Yoojun Nam, Yeri Alice Rim, Ji Hyeon Ju.
      A rare disease is generally defined as a medical condition that affects a small proportion of the population, though specific thresholds vary across countries. Despite regional differences, these definitions consistently reflect the low prevalence of such conditions, the limited availability of effective treatments, and the pressing need for targeted research and regulatory support. As a result of their rarity and low commercial potential, rare diseases have historically represented an area of market failure, where investment and research have been limited and often neglected. However, since the 1990s, each country has guaranteed continuous support to research and development projects to promote the advancements of rare disease treatments, achieving a growth rate greater than that of the entire pharmaceutical industry. In this review, we examine the status of orphan drug development using an advanced therapy medicinal product (ATMP) approach in the growing rare disease market, with a particular focus on cell therapies and gene therapies, which constitute the most actively developed and clinically applied categories within ATMPs. We also explore strategic approaches through which the orphan drug industry can utilize ATMPs, especially these two modalities, to enhance its competitiveness.
    Keywords:  Advanced therapy; Genetic therapy; Orphan drug production; Rare diseases; Regulation; Stem cell therapy
    DOI:  https://doi.org/10.15283/ijsc25028
  12. J Patient Exp. 2025 ;12 23743735251367662
    Hospital Patient and Family Advisory Council Accelerators and Barriers: A Qualitative Study.
    Barbara Lewis, Erika Marquez, Chris Cochran, Neeraj Bhandari, Soumya Upadhyay, Stowe Shoemaker.
      Patient and Family Advisory Councils (PFACs), comprised of patients who have used the hospital's services and their family members, provide hospitals with input on a wide range of initiatives. This qualitative study aims to uncover the facilitators that accelerate and the barriers that inhibit councils and provide hospitals with a blueprint to help them start and strengthen PFACs. Grounded in partnership theory, this exploratory qualitative study used a thematic analysis framework to examine first-person accounts of launching and sustaining a PFAC. The sampling was derived from three groups of potential participants. Participants from 20 hospitals and systems agreed to discuss their councils. Five key themes emerged from the interviews: The PFAC landscape improved after the pandemic, garnering support across the organization is necessary, recruiting ideal members and diversifying the council is critical, effective PFAC operation takes planning, and process and outcome measures can identify the impact and the value of PFACs. Evidence supports patient engagement through PFAC partnerships. However, to ensure a thriving PFAC, the councils require intentional design, diverse participation representing hospital demographics, broad organizational commitment, and systematic evaluation to ensure sustainability and meaningful impact on patient experience and care delivery.
    Keywords:  PFAC; evaluation; outcomes; patient and family advisory council; patient-centered; support
    DOI:  https://doi.org/10.1177/23743735251367662
  13. Stud Health Technol Inform. 2025 Sep 03. 331 265-273
    From Broad Consent to Patient Engagement: A Framework for Consent Management and Study Oversight.
    Anne Pelz, Philipp Heinrich, Gabriele Mueller, Anne Seim, Peter Penndorf, Martin Bialke, Martin Sedlmayr, Ines Reinecke, Markus Wolfien, Katja Hoffmann.
       INTRODUCTION: The German Medical Informatics Initiative (MII) promotes the use of routine clinical data for research, supported by the broad consent framework to ensure patient engagement. This work proposes a data management process and reference infrastructure to improve transparency by enabling patients to track their consent history and data use in research.
    METHODS: We analyzed the data provision process at the University Hospital Dresden (UKD) to identify roles and data flows relevant to secondary data use under broad consent. Established MII tools in use at UKD were evaluated for their suitability in enabling secure data access.
    RESULTS: We developed a structured data access process and implemented a reference infrastructure that lays the groundwork for a potential patient-facing application providing secure access to consent and study details.
    CONCLUSION: The reference infrastructure demonstrates how existing MII tools can be repurposed to offer patient-centric transparency in secondary data use. Future work will address scalability, access control, and ethical considerations, such as patient expectations and the clarity of information.
    Keywords:  Broad Consent; Health Information Exchange; Medical Informatics Applications; Patient Access to Records
    DOI:  https://doi.org/10.3233/SHTI251405
  14. BMC Genomics. 2025 Aug 30. 26(1): 787
    MitoCOMON: whole mitochondrial DNA sequencing by primer design and long overlapping amplicon assembly.
    Yoshikazu Furuta, Manami Kakita, Hidenori Tanaka.
       BACKGROUND: Mitochondrial DNA sequences are used for inter- and intra-specific comparison analysis in ecological studies. Instead of using short regions as marker sequences, analyzing longer regions, such as whole mitochondrial DNA sequences, can improve the accuracy of such studies by increasing the likelihood of detecting species or specific sequences. However, current methods for sequencing whole mitochondrial DNA require primer design for each target species or long fragments of genomic DNA as a PCR template. We developed a method and accompanying tool for PCR-based long-read sequencing of whole mitochondrial DNA, named MitoCOMON, which is applicable to wide-target taxonomic clades and partially digested template DNA.
    RESULTS: PCR amplification of whole mitochondrial DNA as four fragments facilitates the successful assembly of the whole mitochondrial DNA sequence, even when a sample is a mixture of multiple species or partially degraded. The tool that we developed consists of two modules that can design a primer set for species in a target taxonomic clade and assemble the whole mitochondrial DNA sequence from amplicons which were amplified using the designed primer set. Primer sets were designed for mammal and bird species, which showed a high success rate for whole mitochondrial DNA sequencing with high sequence accuracy. Multiple whole mitochondrial DNA sequences were also assembled from samples mixed with the genomic DNA of several species without forming chimeric sequences. In addition to the accuracy, some assembled sequences also retained a long duplication at the D-loop region, suggesting that the method addresses large rearrangements. Compared with a method that amplifies the whole mitochondrial DNA as a single amplicon, our method was effective for partially degraded samples.
    CONCLUSIONS: Our method and accompanying tool, named MitoCOMON, enables an easier acquisition of whole mitochondrial DNA sequences from samples with some DNA degradation without designing species-specific primers. This approach can enhance the accessibility of mitochondrial genomic data and is expected to improve the resolution of ecological analyses, including accurate species identification and individual-level discrimination.
    Keywords:   De Novo assembly; Long reads; Structural variation; Whole mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1186/s12864-025-12010-0
  15. Orphanet J Rare Dis. 2025 Sep 02. 20(1): 471
    Prenatal diagnosis of rare genetic disorders: fourteen years' experience of a tertiary genetic centre from India.
    Jayesh Sheth, Tejasvi Dhondekar, Manali Ajagekar, Chaitanya Datar, Archana Kher, Jigish Trivedi, Swati Thakkar, Ajit Gandhi, Meenakshi Soni, Mayank Chaudhary, Manish Banker, Anil Jalan, Mamta Muranjan, Sujal Munshi, Ami Munshi, Mili Pandya, Jhanvi Shah, Aadhira Nair, Riddhi Bhavsar, Frenny Sheth, Harsh Sheth.
       BACKGROUND: Rare genetic disorders are increasingly diagnosed due to advancing genetic technology, whilst, treatment for them is challenging. Therefore, their prevention by prenatal diagnosis is a way forward to reduce the overall burden. The present study provides an overview of a cohort of patients who were offered prenatal diagnosis for genetic disorders at a tertiary genetic center in India.
    METHODS: The study included 1,738 prenatal samples for the period of 2008 to 2022, identified as being at high risk for rare genetic disorders based on family history, previous affected children, and abnormal ultrasound findings. Participants underwent prenatal diagnostic tests, including chorionic villus sampling or amniocentesis, or fetal blood by various molecular techniques and enzyme-based studies. Data regarding patient demographics, types of disorders screened, and diagnostic outcomes were collected and analyzed.
    RESULTS: Of the 1738 cases, 467 (26.87%) prenatal samples were identified as being affected by genetic anomalies. The diagnosed conditions included hematological disorders (n = 735/1738, 42.28%), inborn errors in metabolism (n = 513/1738, 29.52%), neurological disorders (n = 310/1738, 17.84%), musculoskeletal disorders (n = 45/1738, 2.59%), and other rare genetic disorders (n = 135/1738, 7.77%). Early diagnosis facilitated timely medical information and provided options for prevention, such as medical termination of pregnancy (MTP) in affected cases after genetic counseling.
    CONCLUSION: Our study demonstrates that prenatal diagnosis for rare genetic disorders is an invaluable step toward reducing the burden of these conditions. The use of advanced genetic techniques, combined with genetic counseling, enables effective prevention strategies. However, challenges such as accessibility, cost, and ethical considerations continue to pose barriers to widespread implementation in India. Increased awareness and government policy support are essential to make these diagnostic services universally available and affordable.
    Keywords:  Affordable; Awareness; Diagnosis; Prenatal diagnosis; Prevention; Rare disease; Treatment challenges
    DOI:  https://doi.org/10.1186/s13023-025-04003-9
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