ORCID: https://orcid.org/0000-0002-9789-3129; Ünlütürk, Zeynep ORCID: https://orcid.org/0000-0003-3236-6712; Klopstock, Thomas ORCID: https://orcid.org/0000-0003-2805-4652; Karaa, Amel ORCID: https://orcid.org/0000-0001-5781-9824; Rouzier, Cecile ORCID: https://orcid.org/0000-0002-2969-1904; Domínguez-González, Cristina ORCID: https://orcid.org/0000-0001-5151-988X; Lamperti, Costanza ORCID: https://orcid.org/0000-0002-2280-2253; Mancuso, Michelangelo ORCID: https://orcid.org/0000-0003-2738-8562; Cecchi, Giulia; Montano, Vincenzo ORCID: https://orcid.org/0000-0002-7548-7699; Siciliano, Gabriele ORCID: https://orcid.org/0000-0002-6142-2384; Nicoletta, Valeria ORCID: https://orcid.org/0009-0006-3630-3726; Maioli, Mariantonietta; Primiano, Guido ORCID: https://orcid.org/0000-0001-7616-7008; Servidei, Serenella ORCID: https://orcid.org/0000-0001-8478-2799; La Morgia, Chiara ORCID: https://orcid.org/0000-0002-4639-8929; Carelli, Valerio ORCID: https://orcid.org/0000-0003-4923-6404; Valentino, Maria Lucia ORCID: https://orcid.org/0000-0001-5323-0115; Caporali, Leonardo ORCID: https://orcid.org/0000-0002-0666-4380; Arena, Ignazio Giuseppe; Musumeci, Olimpia ORCID: https://orcid.org/0000-0002-9208-1527; Lopergolo, Diego ORCID: https://orcid.org/0000-0003-2256-0482; Malandrini, Alessandro ORCID: https://orcid.org/0000-0003-1034-0845; Gallus, Gian Nicola ORCID: https://orcid.org/0000-0001-5801-223X; Filosto, Massimiliano ORCID: https://orcid.org/0000-0002-2852-7512; Bello, Luca ORCID: https://orcid.org/0000-0002-3075-6525; Pegoraro, Elena ORCID: https://orcid.org/0000-0002-7740-4156; Comi, Giacomo Pietro ORCID: https://orcid.org/0000-0002-1383-5248; Magri, Francesca ORCID: https://orcid.org/0000-0001-8974-9453; Ronchi, Dario ORCID: https://orcid.org/0000-0002-6093-9816; Di Fonzo, Alessio ORCID: https://orcid.org/0000-0001-6478-026X; Percetti, Marco; Azzimonti, Matteo ORCID: https://orcid.org/0009-0008-7333-6046; Büchner, Boriana ORCID: https://orcid.org/0000-0002-1241-3684; Prokisch, Holger ORCID: https://orcid.org/0000-0003-2379-6286; Bermejo-Guerrero, Laura ORCID: https://orcid.org/0000-0002-8349-715X; Procaccio, Vincent; Gaignard, Pauline ORCID: https://orcid.org/0000-0002-9520-2013; Echaniz-Laguna, Andoni ORCID: https://orcid.org/0000-0003-1012-9783; Schiff, Manuel ORCID: https://orcid.org/0000-0001-8272-232X; Rötig, Agnès ORCID: https://orcid.org/0000-0003-0589-0703; Toutain, Annick; Paquis-Flucklinger, Véronique; Morel, Godelieve; Robin, Stéphanie; Nadaj-Pakleza, Aleksandra ORCID: https://orcid.org/0009-0002-7212-3918; Chanson, Jean-Baptiste; Chaussenot, Annabelle; Ait-El-Mkadem Saadi, Samira; Trimouille, Aurélien; Tranchant, Christine ORCID: https://orcid.org/0000-0002-2895-1292; Salort-Campana, Emmanuelle ORCID: https://orcid.org/0000-0002-1846-3017; Bieth, Eric; Sacconi, Sabrina ORCID: https://orcid.org/0000-0002-0246-1455; Duval, Fanny; Restrepo Vera, Juan Luis; Molnar, Maria Judit; Vissing, John ORCID: https://orcid.org/0000-0001-6144-8544; Haas, Richard ORCID: https://orcid.org/0009-0001-4728-2792; Larson, Austin ORCID: https://orcid.org/0000-0002-2079-6929; Enns, Gregory M.; Parikh, Sumit ORCID: https://orcid.org/0000-0003-3712-8959; Goldstein, Amy ORCID: https://orcid.org/0000-0001-6593-5905 und Hirano, Michio ORCID: https://orcid.org/0000-0002-7070-7402
(2026):
Clinical and Genotypic Spectrum of Twinkle-Related Disorders.
In: Neurology, Bd. 106, Nr. 3, e214401
Abstract
Background and Objectives: Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.
Methods: A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.
Results: The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.
Discussion: This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin > Munich Cluster for Systems Neurology (SyNergy)
Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| ISSN: | 0028-3878 |
| Sprache: | Englisch |
| Dokumenten ID: | 132033 |
| Datum der Veröffentlichung auf Open Access LMU: | 04. Feb. 2026 16:21 |
| Letzte Änderungen: | 04. Feb. 2026 16:21 |
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