Twinkle-related disorders affect the same mitochondrial DNA maintenance pathway as thymidine kinase 2 deficiency (TK2d), and like TK2d often begin with muscle weakness before progressing to involve other organs, according to a large international study of nearly 200 patients published recently in Neurology Journals.
By clarifying how symptoms unfold over time, the findings help patients better understand what to expect from a disease that shares biological roots with other mitochondrial DNA depletion syndromes.
Both Twinkle-related disorders and TK2d disrupt the ability of mitochondria to copy and maintain their DNA, which is essential for energy production. TK2d is caused by mutations in the TK2 gene, while Twinkle disorders arise from variants in the TWNK gene. Although the genes differ, both conditions impair mitochondrial DNA replication, leading to overlapping features such as muscle weakness, fatigue and, in some cases, neurologic involvement.
Researchers from Europe and the United States analyzed medical records from 189 patients with genetically confirmed Twinkle-related disorders. The mean age at symptom onset was 40.3 years, with a wide range from birth to 78 years. At the time of analysis, 70.4% of patients were alive. Most patients, 85.2%, were diagnosed with primary mitochondrial myopathy, a pattern also commonly seen in later-onset forms of TK2 deficiency.
Read more about the signs and symptoms of TK2d
“[T]his extensive 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,” explained this study’s authors.
The most frequent symptom was progressive external ophthalmoplegia, or weakness of the eye muscles, affecting 84.7% of patients. Skeletal muscle weakness or exercise intolerance occurred in 55.6%. Other features included hearing loss in 17.5%, psychiatric symptoms in 15.3%, parkinsonism in 13.8% and ataxia (loss of muscle control) in 12.7%. Similar to TK2d, symptoms outside the muscles reflected the high energy demands of the nervous system and other organs.
Disease patterns changed with time. At onset, 76.8% of patients had mainly neuromuscular symptoms. After eight or more years, neuromuscular involvement declined to 54.4% of patients, while brain and multiorgan involvement each increased to 23.3%. This gradual spread mirrors the progression seen in some individuals with TK2d and highlights why ongoing monitoring is important even when early symptoms seem limited.
Genetic testing revealed 73 TWNK variants, including 16 newly identified. Most patients had one altered copy of the gene, while those with two altered copies typically developed symptoms in early childhood, similar to severe pediatric TK2d. For patients, the results emphasize that Twinkle-related disorders and TK2d are part of a broader family of mitochondrial diseases. Understanding their shared mechanisms may help researchers design future trials and treatments that benefit both groups.
Sign up here to get the latest news, perspectives, and information about TK2d sent directly to your inbox. Registration is free and only takes a minute.