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000284031 037__ $$aDZNE-2026-00074
000284031 041__ $$aEnglish
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000284031 1001_ $$00000-0002-9789-3129$$aLopriore, Piervito$$b0
000284031 245__ $$aClinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
000284031 260__ $$aPhiladelphia, Pa.$$bWolters Kluwer$$c2026
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000284031 520__ $$aTwinkle, 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.
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000284031 650_7 $$0EC 3.6.4.12$$2NLM Chemicals$$aTWNK protein, human
000284031 650_7 $$2NLM Chemicals$$aMitochondrial Proteins
000284031 650_7 $$0EC 3.6.4.-$$2NLM Chemicals$$aDNA Helicases
000284031 650_2 $$2MeSH$$aHumans
000284031 650_2 $$2MeSH$$aFemale
000284031 650_2 $$2MeSH$$aMale
000284031 650_2 $$2MeSH$$aAdult
000284031 650_2 $$2MeSH$$aMiddle Aged
000284031 650_2 $$2MeSH$$aRetrospective Studies
000284031 650_2 $$2MeSH$$aAdolescent
000284031 650_2 $$2MeSH$$aChild
000284031 650_2 $$2MeSH$$aPhenotype
000284031 650_2 $$2MeSH$$aGenotype
000284031 650_2 $$2MeSH$$aYoung Adult
000284031 650_2 $$2MeSH$$aMitochondrial Diseases: genetics
000284031 650_2 $$2MeSH$$aMitochondrial Diseases: physiopathology
000284031 650_2 $$2MeSH$$aCohort Studies
000284031 650_2 $$2MeSH$$aMitochondrial Proteins: genetics
000284031 650_2 $$2MeSH$$aAged
000284031 650_2 $$2MeSH$$aChild, Preschool
000284031 650_2 $$2MeSH$$aMutation
000284031 650_2 $$2MeSH$$aAge of Onset
000284031 650_2 $$2MeSH$$aMitochondrial Myopathies: genetics
000284031 650_2 $$2MeSH$$aDNA Helicases
000284031 7001_ $$00000-0003-3236-6712$$aÜnlütürk, Zeynep$$b1
000284031 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b2
000284031 7001_ $$00000-0001-5781-9824$$aKaraa, Amel$$b3
000284031 7001_ $$00000-0002-2969-1904$$aRouzier, Cecile$$b4
000284031 7001_ $$00000-0001-5151-988X$$aDomínguez-González, Cristina$$b5
000284031 7001_ $$00000-0002-2280-2253$$aLamperti, Costanza$$b6
000284031 7001_ $$00000-0003-2738-8562$$aMancuso, Michelangelo$$b7
000284031 7001_ $$aReadiness, Twinkle-Related Disorders International Consortium for Trial$$b8$$eCollaboration Author
000284031 7001_ $$aCecchi, Giulia$$b9
000284031 7001_ $$00000-0002-7548-7699$$aMontano, Vincenzo$$b10
000284031 7001_ $$00000-0002-6142-2384$$aSiciliano, Gabriele$$b11
000284031 7001_ $$00009-0006-3630-3726$$aNicoletta, Valeria$$b12
000284031 7001_ $$aMaioli, Mariantonietta$$b13
000284031 7001_ $$00000-0001-7616-7008$$aPrimiano, Guido$$b14
000284031 7001_ $$00000-0001-8478-2799$$aServidei, Serenella$$b15
000284031 7001_ $$00000-0002-4639-8929$$aLa Morgia, Chiara$$b16
000284031 7001_ $$00000-0003-4923-6404$$aCarelli, Valerio$$b17
000284031 7001_ $$00000-0001-5323-0115$$aValentino, Maria Lucia$$b18
000284031 7001_ $$00000-0002-0666-4380$$aCaporali, Leonardo$$b19
000284031 7001_ $$aArena, Ignazio Giuseppe$$b20
000284031 7001_ $$00000-0002-9208-1527$$aMusumeci, Olimpia$$b21
000284031 7001_ $$00000-0003-2256-0482$$aLopergolo, Diego$$b22
000284031 7001_ $$00000-0003-1034-0845$$aMalandrini, Alessandro$$b23
000284031 7001_ $$00000-0001-5801-223X$$aGallus, Gian Nicola$$b24
000284031 7001_ $$00000-0002-2852-7512$$aFilosto, Massimiliano$$b25
000284031 7001_ $$00000-0002-3075-6525$$aBello, Luca$$b26
000284031 7001_ $$00000-0002-7740-4156$$aPegoraro, Elena$$b27
000284031 7001_ $$00000-0002-1383-5248$$aComi, Giacomo Pietro$$b28
000284031 7001_ $$00000-0001-8974-9453$$aMagri, Francesca$$b29
000284031 7001_ $$00000-0002-6093-9816$$aRonchi, Dario$$b30
000284031 7001_ $$00000-0001-6478-026X$$aDi Fonzo, Alessio$$b31
000284031 7001_ $$aPercetti, Marco$$b32
000284031 7001_ $$00009-0008-7333-6046$$aAzzimonti, Matteo$$b33
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000284031 7001_ $$00000-0003-1012-9783$$aEchaniz-Laguna, Andoni$$b39
000284031 7001_ $$00000-0001-8272-232X$$aSchiff, Manuel$$b40
000284031 7001_ $$00000-0003-0589-0703$$aRötig, Agnès$$b41
000284031 7001_ $$aToutain, Annick$$b42
000284031 7001_ $$aPaquis-Flucklinger, Véronique$$b43
000284031 7001_ $$aMorel, Godelieve$$b44
000284031 7001_ $$aRobin, Stéphanie$$b45
000284031 7001_ $$00009-0002-7212-3918$$aNadaj-Pakleza, Aleksandra$$b46
000284031 7001_ $$aChanson, Jean-Baptiste$$b47
000284031 7001_ $$aChaussenot, Annabelle$$b48
000284031 7001_ $$aAit-El-Mkadem Saadi, Samira$$b49
000284031 7001_ $$aTrimouille, Aurélien$$b50
000284031 7001_ $$00000-0002-2895-1292$$aTranchant, Christine$$b51
000284031 7001_ $$00000-0002-1846-3017$$aSalort-Campana, Emmanuelle$$b52
000284031 7001_ $$aBieth, Eric$$b53
000284031 7001_ $$00000-0002-0246-1455$$aSacconi, Sabrina$$b54
000284031 7001_ $$aDuval, Fanny$$b55
000284031 7001_ $$aRestrepo Vera, Juan Luis$$b56
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000284031 7001_ $$00000-0001-6144-8544$$aVissing, John$$b58
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