bims-tyki2d 2026-03-08 papers

Nat Biotechnol. 2026 Mar 02.

Mitochondrion. 2026 Feb 28. pii: S1567-7249(26)00028-0. [Epub ahead of print]89 102138

Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy.

Hacer Durmus, Asuman Gedikbaşı, Serdar Ceylaner, Arman Çakar, Sezan Mergen, Esen Kıyan, Yesim Gülşen Parman.

OBJECTIVE: To evaluate the long-term efficacy and safety of deoxynucleoside therapy in adult patients with late-onset thymidine kinase 2 deficiency (TK2d).
BACKGROUND: TK2d is a mitochondrial myopathy causing progressive weakness, respiratory insufficiency, and early mortality. While nucleoside supplementation benefits pediatric cases, evidence in adults remains limited.
METHODS: Six genetically confirmed adults with TK2d were treated under compassionate-use protocols in Turkey, receiving escalating doses of oral or PEG-administered Doxecitine and Doxribtimine up to 800 mg/kg/day. Functional and clinical outcomes included the 6-minute walk test (6MWT), Hammersmith Functional Motor Scale Expanded (HFMSE), forced vital capacity (FVC), Fatigue Severity Scale (FSS), and body mass index (BMI).
RESULTS: Over a median follow-up of 24 (range 6-36) months, therapy was associated with sustained functional and respiratory improvements. Mean 6MWT increased from 152 m at baseline to 468 m at 24 months and exceeded 600 m in patients with 36-month data. The mean HFMSE increased from 20.5 at baseline to 24.5 at 3 months, 29 at 6 months. Patients with the longest follow-up reached a mean HFMSE of 58 at 36 months. FVC, which had declined before treatment, stabilized or improved in all patients (mean increase from 36% to 55.6% at 36 months). The youngest patient achieved near-normal respiratory function. Fatigue severity decreased by ∼ 30%, and BMI improved notably in underweight individuals. Treatment was generally well tolerated; transient liver enzyme elevations and mild gastrointestinal side effects resolved spontaneously.
CONCLUSIONS: Deoxynucleoside therapy appears effective and well tolerated in adults with TK2d, producing sustained functional and respiratory gains. Early treatment initiation is crucial to maximize benefit; though partial improvements may occur even in advanced disease.

Keywords: Deoxynucleoside Therapy; Late-onset; TK2 deficiency

DOI: https://doi.org/10.1016/j.mito.2026.102138

Hum Genet. 2026 Mar 05. pii: 29. [Epub ahead of print]145(1):

Genomics workforce views on automating genomic reanalysis: trust, equity and governance.

Emily A King, Fiona Lynch, Zornitza Stark, Danya F Vears.

DOI: https://doi.org/10.1007/s00439-026-02824-7

Genet Med. 2026 Jan;pii: S1098-3600(25)00267-9. [Epub ahead of print]28(1): 101620

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

Thiloka Ratnaike, Siddharth Ramanan, Nour Elkhateeb, Ramya Narayanan, Jenny Yang, Eszter Sara Arany, Manya Mirchandani, Rachael Piper, Katherine Schon, M Eren Kule, Christopher Gilmartin, Angela Lochmüller, Emogene Shaw, Rita Horváth, Patrick F Chinnery.

PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Keywords: HPO; Mitochondrial disease; Phenotype similarity; Rare disease; UMAP

DOI: https://doi.org/10.1016/j.gim.2025.101620

BMJ. 2026 Mar 03. 392 s432

Rare diseases: NICE lays out quality standard to improve diagnosis and treatment.

Jacqui Wise.

DOI: https://doi.org/10.1136/bmj.s432