bims-tyki2d 2026-01-25 papers

Issue of 2026–01–25
three papers selected by
Zoya Panahloo, UCB

J Inherit Metab Dis. 2026 Jan;49(1): e70147

Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.

Paloma Martín-Jimenez, Laura Bermejo-Guerrero, Luz Edith Ochoa, María Navarro-Riquelme, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, Adrián González Quintana, Ana Bermejo-Moriñigo, Violeta González-Méndez, Cristina Martín-Arriscado Arroba, Dimitrii Smirnov, Nikita Konstantinovskiy, Joaquín Arenas, Miguel Ángel Martin, Alberto Blázquez, Cristina Domínguez-González.

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.

Keywords: GDF15; TK2 deficiency; biomarkers; late‐onset; mitochondrial myopathy; natural history

DOI: https://doi.org/10.1002/jimd.70147

Adv Sci (Weinh). 2026 Jan 22. e23368

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.

Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.

Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.

Keywords: chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics

DOI: https://doi.org/10.1002/advs.202523368

Am J Med Genet A. 2026 Jan 20.

Denial of Inpatient Genetic Testing: A Study on Outpatient Yield and Outcomes.

Cindy Y Canales, Kathleen Shields, Meagan Choates, Paul Hillman, Laura Farach, Theresa Wittman, Kathryn Leal.

Genetic conditions suspected in children often require genetic testing for accurate diagnoses, but testing remains costly. Case management teams review genetic test requests to improve access for patients while reducing the financial burden for medical institutions. Limited data exist on the diagnostic yields of genetic testing in the inpatient versus outpatient setting and the impact to care denial of inpatient genetic testing may pose. This study investigates diagnostic yields between patients approved for versus denied inpatient genetic testing and its impact to care. One thousand and fifty-two charts of children admitted inpatient who received a genetic consult between July 2018 and June 2023 were reviewed; charts of children that followed up at the outpatient genetics clinic after inpatient discharge were additionally reviewed. Collected data included recommendations, completion, and results of genetic testing, and management recommendations based on a diagnosis. Statistical analysis assessed differences between the groups. Private insurance holders and patients with no prematurity history were less likely to be approved for inpatient genetic testing. The outpatient group had nearly twice the diagnostic yield and management recommendations did not differ between the groups. Inclusion of genetic providers in the review of inpatient genetic testing requests should be considered to improve outcomes.

Keywords: approval; case management; denial; diagnostic yield; genetic testing; inpatient; outpatient

DOI: https://doi.org/10.1002/ajmga.70041