Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
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Lopriore Piervito, Ünlütürk Zeynep, Klopstock Thomas, Karaa Amel, Rouzier Cecile, Domínguez-González Cristina, Lamperti Costanza, Mancuso Michelangelo, Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC), Cecchi Giulia, Montano Vincenzo, Siciliano Gabriele, Nicoletta Valeria, Maioli Mariantonietta, Primiano Guido, Servidei Serenella, La Morgia Chiara, Carelli Valerio, Valentino Maria Lucia, Caporali Leonardo, Arena Ignazio Giuseppe, Musumeci Olimpia, Lopergolo Diego, Malandrini Alessandro, Gallus Gian Nicola, Filosto Massimiliano, Bello Luca, Pegoraro Elena, Comi Giacomo Pietro, Magri Francesca, Ronchi Dario, Di Fonzo Alessio, Percetti Marco, Azzimonti Matteo, Büchner Boriana, Prokisch Holger, Bermejo-Guerrero Laura, Procaccio Vincent, Gaignard Pauline, Echaniz-Laguna Andoni, Schiff Manuel, Rötig Agnès, Toutain Annick, Paquis-Flucklinger Véronique, Morel Godelieve, Robin Stéphanie, Nadaj-Pakleza Aleksandra, Chanson Jean-Baptiste, Chaussenot Annabelle, Ait-El-Mkadem Saadi Samira, Trimouille Aurélien, Tranchant Christine, Salort-Campana Emmanuelle, Bieth Eric, Sacconi Sabrina, Duval Fanny, Restrepo Vera Juan Luis, Molnar Maria Judit, Vissing John, Haas Richard, Larson Austin, Enns Gregory M, Parikh Sumit, Goldstein Amy, Hirano Michio
Аннотация
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.