ETD

• Cohort study.
• Genotype
• Primary mitochondrial diseases
• Twinkle
• Twinkle-related disorders
• TWNK

Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase essential for genome replication and integrity. Twinkle-related disorders are a heterogeneous group of mitochondrial diseases with an incompletely defined clinical and molecular spectrum. This study aimed to characterize phenotypic and genotypic variability in a multinational cohort.
A retrospective cohort study was conducted on 189 patients (116 females) from centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, within the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Clinical, demographic, and genetic data were collected. Phenotypes included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy, multisystem involvement, undetermined forms and asymptomatic carriers.
The mean age at onset was 40.3 years, and 70.4% of patients were alive at the time of analysis. Primary mitochondrial myopathy was predominant (85.2%), with progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%) as leading features, followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Neuromuscular features were most common at onset (76.8%), later progressing to central nervous system (23.3%) and multisystem involvement (23.3%). A total of 73 TWNK variants were identified, 16 novel, mostly missense, clustering in functionally critical domains.
This study refines the clinical spectrum of Twinkle-related disorders, identifies pathogenic mutational hotspots, and emphasizes the value of international collaborations like TReDIC for advancing knowledge and preparing future clinical trials.