bims-tyki2d 2026-04-12 papers

bims-tyki2d

Biomed News

on Thymidine kinase 2 deficiency

Issue of 2026–04–12
ten papers selected by
Zoya Panahloo, UCB

Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.
Reframing AI for Rare Disease Recognition.
The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.
Ophthalmic manifestations of mitochondrial disorders.
Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.
Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy.
Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.
Regional Barriers to Advancing Genetic Medicine in Japan: Insights from a Shizuoka Prefecture Survey.
Identification of the Genetic Causes of Inherited Diseases in a North African Biobank: Implications for Genetic Diagnosis.
Virtual Virtues: Is it Ethical to Search Patients on Social Media?

J Neuromuscul Dis. 2026 Apr 07. 22143602261433223

Transforming the natural course of infantile onset thymidine kinase 2 deficiency through early nucleoside replacement therapy.

Gulcin Akinci, Javid Sardarzada, Haluk Topaloglu.

   BACKGROUND: Thymidine kinase 2 (TK2) deficiency is an ultra-rare, severe mitochondrial myopathy caused by pathogenic variants in TK2 and characterized by a wide range of ages at onset. The infantile form, presenting before 2 years of age, is the most rapidly progressive and is associated with a high risk of early mortality. We describe the clinical outcomes of early nucleoside therapy in a series of children with infantile-onset TK2 deficiency.
METHODS: We retrospectively reviewed four children with genetically confirmed infantile-onset TK2 deficiency treated with oral deoxycytidine/deoxythymidine (dC/dT) through an Early Access Program at two centers. Dosing was escalated to 800 mg/kg/day as tolerated. Patients were followed at baseline, Month 1, and regular intervals thereafter. Outcomes included neurological examinations, eight motor milestones, and respiratory and feeding support. Safety laboratory results, neuroimaging, and biopsy findings were reviewed.
RESULTS: Treatment began at 19-24 months (median duration 26 months; range: 4-81). All presented within the first year with hypotonia, motor regression, and respiratory and/or bulbar involvement. Two required invasive ventilation and three required tube feeding before therapy. After dC/dT initiation, all improved with no further milestone loss. Three achieved independent ambulation and stair climbing; the fourth, at 4 months of therapy, has begun unassisted walking. Both tracheostomized patients were weaned from ventilation, and enteral feeding was discontinued in all three within 1-6 months. Only mild dose-related diarrhea occurred in one patient.
CONCLUSION: Early nucleoside therapy halts disease progression and restores motor function in infantile-onset TK2 deficiency, the most severe form of the disease.

Keywords:  infantile-onset; mitochondrial myopathy; mtDNA depletion syndrome; nucleoside therapy; thymidine kinase 2 deficiency

DOI:  https://doi.org/10.1177/22143602261433223
Res Sq. 2026 Apr 02. pii: rs.3.rs-9036259. [Epub ahead of print]

Reframing AI for Rare Disease Recognition.

Wei-Qi Wei, Chao Yan, Wu-Chen Su, Yi Xin, Monika Grabowska, Vern Kerchberger, Victor Borza, Jinlian Wang, Liwei Wang, Rui Li, Jacob Lynn, Alyson Dickson, Cathy Shyr, QiPing Feng, C Stein, Kai Wang, Peter Embí, Bradley Malin, Hongfang Liu.

Rare diseases affect over 300 million people worldwide, yet patients often endure years-long diagnostic delays that limit timely intervention and trial opportunities. Computational rare disease recognition (RDR) remains constrained by knowledge resources that are often incomplete, heterogeneous, and dependent on extensive multi-disciplinary expert curation that cannot scale. Large language models (LLMs) applied directly for end-to-end diagnosis or disease discrimination face similar knowledge bottlenecks while also raising concerns around cost, reproducibility, and data governance. Here, we introduce GEN-KnowRD, a knowledge-layer-first framework that leverages LLMs to generate schema-guided rare disease profiles, systematically assesses their quality, and constructs a computable knowledge base (PheMAP-RD) for local deployment. GEN-KnowRD integrates this knowledge into lightweight inference pipelines for both general-purpose disease screening and specialized early discrimination from longitudinal electronic health records. In tests using six public benchmarks for general-purpose screening (9,290 patients spanning 798 rare diseases), GEN-KnowRD substantially improved disease ranking versus 1) a state-of-the-art, HPO-centered diagnostic framework (up to 345.8% improvement in top-1 success), 2) advanced end-to-end LLM reasoning (up to 129.1% improvement), and 3) a variant of GEN-KnowRD instantiated with expert-curated knowledge rather than LLM-generated profiles. In two real-world cohorts for early diagnosis of idiopathic pulmonary fibrosis (511 patients) as a use case, GEN-KnowRD also demonstrated robust discrimination performance gains, supporting effective RDR during the pre-diagnostic window. These findings demonstrate that repositioning LLMs from diagnostic reasoning to the knowledge layer-decoupling knowledge construction from patient-level inference-yields stronger RDR, while providing scalable, continuously updatable, and reusable infrastructure for diagnosis, screening, and clinical research across the rare disease landscape.

DOI: https://doi.org/10.21203/rs.3.rs-9036259/v1
Per Med. 2026 Apr 04. 1-8

The role of real-world data and real-world evidence in advancing regulatory science and targeted therapeutics: a narrative review from the United States perspective.

Emily Nagel, Youssef M Roman.

  Randomized controlled trials (RCTs) encounter feasibility gaps when addressing rare genetic disorders and molecularly defined patient subgroups. The U.S. Food and Drug Administration has increasingly integrated real-world evidence (RWE) into the regulatory lifecycle. The objective of this article is to analyze the regulatory evolution following the 21st Century Cures Act and evaluate landmark drug approvals and expansions where real-world data (RWD) provided the primary or supplementary evidentiary foundation. A structured search of electronic databases, including PubMed, Embase, and Web of Science, was performed to identify relevant peer-reviewed articles. The tumor-agnostic approval of pembrolizumab demonstrated how RWE can establish clinical utility across multiple cancer types sharing specific biomarkers. For rare diseases like N-acetylglutamate synthase deficiency (carglumic acid), RWE provided essential external comparators where RCTs were impossible. In cystic fibrosis (ivacaftor), the U.S. Cystic Fibrosis Foundation Patient Registry facilitated indication expansions to ultra-rare genetic variants through longitudinal real-world outcomes. RWE proved vital for post-market surveillance in populations typically excluded from trials. While technical challenges in data interoperability and ethical concerns regarding genomic privacy remain, RWE offers a dynamic model that accelerates access to targeted therapies. The integration of high-fidelity RWD ensures that the safety and efficacy of precision medicines are validated within the complex global clinical practice.

Keywords:  Real-world evidence; U.S. food and drug administration; data governance; drug development; pharmacovigilance; precision medicine; real-world data; regulatory affairs

DOI:  https://doi.org/10.1080/17410541.2026.2655298
Prog Retin Eye Res. 2026 Apr 03. pii: S1350-9462(26)00032-7. [Epub ahead of print] 101466

Ophthalmic manifestations of mitochondrial disorders.

Megan F Baxter, Grace A Borchert, Emma L Blakely, Claire W Ruan, Robert E MacLaren, Robert McFarland, Robert W Taylor.

  Mitochondrial diseases are the most common group of inherited neurometabolic disorders and frequently involve multiple organ systems with high energy demands. Ophthalmic manifestations are a common occurrence in affected individuals and may be the earliest or predominant clinical feature. However, the marked clinical heterogeneity of mitochondrial eye disease often delays recognition and therefore diagnosis. Mitochondria play a central role in cellular metabolism through the process of oxidative phosphorylation. Genetic mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can impair this key metabolic process leading to clinical disease. Diagnosing such mitochondrial diseases is however often complicated - the same genetic change can result in different symptoms (variable expressivity); different genes can cause similar conditions (allelic and locus heterogeneity); a single genetic change may affect multiple body systems (pleiotropy); and the proportion of affected mitochondrial DNA molecules can vary between tissues (mtDNA heteroplasmy). While the diagnostic process will certainly be influenced by the initial clinical presentation, perhaps more important is clinician awareness and early consideration of an underlying mitochondrial disorder. Early and accurate molecular genetic diagnosis is both available and essential, not only for prognostication and management, but also for reproductive counselling, access to appropriate clinical trials, cascade testing of relevant family members and consideration of emerging mitochondrial therapeutics(1,2). In this review, we summarise the biochemical and genetic foundations of mitochondrial eye disease, describe the spectrum of clinical phenotypes, outline diagnostic approaches and considerations, and highlight the importance of precise early diagnosis in guiding management and reproductive decision-making.

Keywords:  mitochondria; mitochondrial counselling; ophthalmology

DOI:  https://doi.org/10.1016/j.preteyeres.2026.101466
Orphanet J Rare Dis. 2026 Apr 09. pii: 143. [Epub ahead of print]21(1):

Diagnosis of pediatric mitochondrial diseases via targeted next-generation sequencing (NGS): real-world data with the Blueprint Genetics® platform.

Annamaria Sapuppo, Grete Francesca Privitera, Vincenzo Sortino, Piero Pavone, Agata Polizzi, Martino Ruggieri, Raffaele Falsaperla.



Keywords:  Blueprint genetics; Buccal swab; Clinical phenotype; Diagnostic sensitivity; Early onset; Mitochondrial diseases; Next-generation sequencing; Pediatric neurology

DOI:  https://doi.org/10.1186/s13023-026-04213-9
Health Technol (Berl). 2026 Mar 10.

Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy.

Mai-Lan Ho, Marinka Zitnik, Ronen Azachi, Sanjay Basu, Pranav Rajpurkar, Richard Sidlow.

   Purpose: To summarize current challenges in rare disease (RD) diagnosis and therapy, highlight recent advances in artificial intelligence (AI) for RDs, and propose a model future state for RD patient care.
Methods: Multidisciplinary expert-led narrative review summarizing modern practical challenges and rate-limiting steps in RD patient care, citing key clinical and research considerations with respect to regulatory and economic constraints.
Results: Over 10,000 known RDs collectively affect 1 in 10 Americans, a total of over 30 million people. Annually, RDs account for over $1 trillion of annual US healthcare expenditures. Despite advances in genomic medicine, it takes 5-8 years on average to obtain an accurate diagnosis, and less than 5% of RDs currently have FDA-approved therapies. In this article, we review the history of RD diagnosis and current healthcare gaps underlying the major failures in patient care. Next, we will highlight emerging advances in genomic medicine and AI that are rapidly changing the RD landscape. Finally, we propose a target future state that integrates agentic AI for diagnosis and therapy with human-in-the-loop feedback.
Conclusions: The rare disease diagnostic and therapeutic odyssey represents healthcare's most persistent failure mode. Ongoing challenges for clinical implementation involve biological modeling, manufacturing bottlenecks, and clinical trial design. We propose strategies for artificial intelligence to restructure the traditional sequence of diagnosis-then-therapy into a proactive orchestrated system delivering personalized cures at scale.

Keywords:  Artificial intelligence; Genetic; Genome; Omics; Orphan; Rare

DOI:  https://doi.org/10.1007/s12553-026-01057-y
J Neurol. 2026 Apr 10. pii: 263. [Epub ahead of print]273(5):

Non-invasive biomarkers for diagnosis and monitoring of primary mitochondrial diseases.

Ignazio Giuseppe Arena, Shamini Saravanabavan, Rita Horvath, Jelle van den Ameele.

  Primary mitochondrial diseases (PMDs) represent a clinically and genetically heterogeneous group of disorders characterized by impaired oxidative phosphorylation and multisystem involvement, commonly affecting the nervous system. As therapeutic development accelerates, there is a growing need for robust biomarkers capable of supporting diagnosis, stratifying patient subgroups, monitoring disease progression, and providing sensitive pharmacodynamic readouts for clinical trials. This review summarizes recent advances in three major non-invasive biomarker domains relevant to PMDs: circulating serum and molecular biomarkers, functional and digital endpoints, and neuroimaging modalities. Circulating markers, such as FGF21, GDF15, NfL, and NAD⁺-related signatures, have each been proposed for diagnosis and to follow disease progression, while multi-omics approaches are paving the way toward integrated molecular phenotyping. Digital health technologies, including accelerometry and gait analytics, enable objective quantification of real-world functional impairment, although disease-specific validation remains an unmet need. Neuroimaging offers mechanistic insights through metabolic (MRS, CEST), perfusion (ASL), and molecular modalities (mitochondrial PET tracers). Cutting-edge tools, such as Multi-Spectral Optoacoustic Tomography (MSOT), Raman spectroscopy, and Near-Infrared Spectroscopy (NIRS), promise real-time or spatially resolved assessment of mitochondrial function. Together, these developments outline multidimensional biomarker approaches for PMDs, with the potential to directly measure target engagement and clinically meaningful phenotypes in future therapeutic trials. Future progress will depend on longitudinal validation, harmonized acquisition protocols, and the integration of multimodal platforms to support upcoming therapeutic trials and precision medicine strategies.

Keywords:  Biomarkers; Clinical trials; Digital health technologies; Functional endpoints; Magnetic resonance imaging; Mitochondrial disease; Neuroimaging; Phenotyping; Positron emission tomography; Precision medicine; Wearable devices

DOI:  https://doi.org/10.1007/s00415-026-13794-1
JMA J. 2026 Mar 16. 9(2): 525-534

Regional Barriers to Advancing Genetic Medicine in Japan: Insights from a Shizuoka Prefecture Survey.

Kou Sueoka, Yuki Mizuguchi, Yasue Horiuchi, Takeshi Usui, Osamu Mochizuki, Hidehiko Miyake, Yuichi Goto.

   Introduction: The expansion of genetic medicine in Japan has created an urgent need for regionally-adaptable systems to ensure equitable implementation. This study examines challenges in developing a sustainable framework for regional genetic medicine, using Shizuoka Prefecture-a non-metropolitan area with average socioeconomic indicators-as a case model.
Methods: A two-phase survey was conducted between December 2023 and January 2024. The first phase involved a questionnaire sent to 44 major medical institutions and all board-certified clinical genetics specialists in the prefecture. In the second phase, 20 of the responding institutions completed a more detailed follow-up survey. The surveys assessed human resource capacity, institutional collaboration, and the adoption of digital infrastructure.
Results: The results revealed critical shortages in clinical geneticists, certified genetic counselors, and genetic nursing specialists. Inter-institutional collaboration was limited, with few systems in place for data sharing or regional coordination. Digital tools, such as remote consultation systems and information platforms, were underutilized. Respondents identified the need for shared infrastructure, better communication among institutions, and flexible strategies to address geographic and systemic barriers.
Conclusions: This study highlights the urgent need for network-based infrastructure and a specialized workforce to support the expansion of genetic medicine in regional settings. The findings from Shizuoka are likely reflective of broader national challenges and underscore the importance of policy and system-level interventions to promote equitable access to genetic healthcare across Japan.

Keywords:  Board of Medical Genetics and Genomics; designated intractable diseases; digital transformation; genetic counselor; online counseling

DOI:  https://doi.org/10.31662/jmaj.2025-0240
Mol Syndromol. 2026 Apr;17(2): 101-111

Identification of the Genetic Causes of Inherited Diseases in a North African Biobank: Implications for Genetic Diagnosis.

Majida Charif, Saida Lhousni, Ayad Ghanam, Maria Rkain, Noufissa Benajiba, Rim Amrani, Abdeladim Babakhouya, Sahar Messaoudi, Aziza Elouali, Anass Ayyad, Abdeljaouad Najib, Omar El Mahi, Adnane Benzirar, Mehdi Moutaouekkil, Sanae Allaoui, Mohammed Benahmed, Manal Elidrissi Errahhali, Mounia Elidrissi Errahhali, Aymane Bouzidi, Meryem Ouarzane, Antony T Vincent, Adnane Sellam, Guy Lenaers, Redouane Boulouiz, Mohammed Bellaoui.

   Introduction: In North Africa, genetic diseases are widespread but under-studied due to limited research resources. This study used exome sequencing to identify disease-causing variants in a large series of Moroccan patients with suspected genetic diseases.
Methods: A cohort of 30 patients with genetic diseases from the BRO Biobank underwent exome sequencing. Candidate variants were evaluated by segregation analysis and molecular modeling.
Results: Thirty-one variants were identified in 27 known genes. Interestingly, 54.8% of these variants were novel and therefore could be specific to the Moroccan population. Pathogenic or likely pathogenic disease-causing variants were identified in 22 of 30 patients, leading to a genetic testing yield of 73.3%. Moreover, the identified variants, classified as of uncertain significance, likely benign or benign, were predicted to alter protein structure using in silico modeling of 3D protein structure. The diagnosis was changed in 23% of patients with suspected genetic syndromes, and the etiology was determined in all patients with unrecognizable genetic disorder.
Conclusion: This study represents the largest biobank-based study of inherited diseases in a North African country. It illustrates the genetic variability of the Moroccan population and improves our understanding of genotype-phenotype correlations. Furthermore, the relatively high yield of genetic testing obtained in this study justifies the need to implement exome sequencing in the clinical setting in Morocco for better genetic diagnosis.

Keywords:  BRO Biobank; Exome sequencing; Genetic diseases; Genetic testing yield; North African population

DOI:  https://doi.org/10.1159/000546908
Focus (Am Psychiatr Publ). 2026 Jan;24(1): 62-64

Virtual Virtues: Is it Ethical to Search Patients on Social Media?

Zoya Munsar, Chaden Noureddine, Jacob M Appel.

  As social media becomes increasingly intertwined with everyday life, psychiatrists face new ethical challenges when navigating patients' online presence. Although patients' social media can offer valuable collateral information for psychiatrists, especially in high-risk or unclear clinical situations, accessing this content without consent risks undermining trust, breaching boundaries, and introducing bias. To preserve the therapeutic alliance in an evolving digital age, the field of psychiatry must establish clear, ethically grounded guidelines for when and how to engage with patients' social media. The objectives of this article are to explore the ethical, clinical, and legal implications for psychiatrists when accessing patients' social media, and to propose strategies for integrating digital boundaries into psychiatric practice.

Keywords:  Ethics; Media; Sociopolitical Issues; Technology

DOI:  https://doi.org/10.1176/appi.focus.20250026