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@ARTICLE{Lopriore:284031,
      author       = {Lopriore, Piervito and Ünlütürk, Zeynep and Klopstock,
                      Thomas and Karaa, Amel and Rouzier, Cecile and
                      Domínguez-González, Cristina and Lamperti, Costanza and
                      Mancuso, Michelangelo and Cecchi, Giulia and Montano,
                      Vincenzo and Siciliano, Gabriele and Nicoletta, Valeria and
                      Maioli, Mariantonietta and Primiano, Guido and Servidei,
                      Serenella and La Morgia, Chiara and Carelli, Valerio and
                      Valentino, Maria Lucia and Caporali, Leonardo and Arena,
                      Ignazio Giuseppe and Musumeci, Olimpia and Lopergolo, Diego
                      and Malandrini, Alessandro and Gallus, Gian Nicola and
                      Filosto, Massimiliano and Bello, Luca and Pegoraro, Elena
                      and Comi, Giacomo Pietro and Magri, Francesca and Ronchi,
                      Dario and Di Fonzo, Alessio and Percetti, Marco and
                      Azzimonti, Matteo and Büchner, Boriana and Prokisch, Holger
                      and Bermejo-Guerrero, Laura and Procaccio, Vincent and
                      Gaignard, Pauline and Echaniz-Laguna, Andoni and Schiff,
                      Manuel and Rötig, Agnès and Toutain, Annick and
                      Paquis-Flucklinger, Véronique and Morel, Godelieve and
                      Robin, Stéphanie and Nadaj-Pakleza, Aleksandra and Chanson,
                      Jean-Baptiste and Chaussenot, Annabelle and Ait-El-Mkadem
                      Saadi, Samira and Trimouille, Aurélien and Tranchant,
                      Christine and Salort-Campana, Emmanuelle and Bieth, Eric and
                      Sacconi, Sabrina and Duval, Fanny and Restrepo Vera, Juan
                      Luis and Molnar, Maria Judit and Vissing, John and Haas,
                      Richard and Larson, Austin and Enns, Gregory M and Parikh,
                      Sumit and Goldstein, Amy and Hirano, Michio},
      collaboration = {Readiness, Twinkle-Related Disorders International
                      Consortium for Trial},
      title        = {{C}linical and {G}enotypic {S}pectrum of
                      {T}winkle-{R}elated {D}isorders: {I}nsights {F}rom a
                      {M}ultinational {C}ohort {S}tudy.},
      journal      = {Neurology},
      volume       = {106},
      number       = {3},
      issn         = {0028-3878},
      address      = {Philadelphia, Pa.},
      publisher    = {Wolters Kluwer},
      reportid     = {DZNE-2026-00074},
      pages        = {e214401},
      year         = {2026},
      abstract     = {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.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.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.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.},
      keywords     = {Humans / Female / Male / Adult / Middle Aged /
                      Retrospective Studies / Adolescent / Child / Phenotype /
                      Genotype / Young Adult / Mitochondrial Diseases: genetics /
                      Mitochondrial Diseases: physiopathology / Cohort Studies /
                      Mitochondrial Proteins: genetics / Aged / Child, Preschool /
                      Mutation / Age of Onset / Mitochondrial Myopathies: genetics
                      / DNA Helicases / TWNK protein, human (NLM Chemicals) /
                      Mitochondrial Proteins (NLM Chemicals) / DNA Helicases (NLM
                      Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41538773},
      doi          = {10.1212/WNL.0000000000214401},
      url          = {https://pub.dzne.de/record/284031},
}