Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study

Area of Science:

• Genetics
• Mitochondrial Biology
• Neurology

Background:

• Twinkle (TWNK) is a crucial mitochondrial DNA helicase.
• Twinkle-related disorders are rare genetic conditions causing mitochondrial dysfunction.
• The full clinical and molecular spectrum of these disorders is not well-defined.

Purpose of the Study:

• To characterize the phenotypic and genotypic variability in multinational patients with Twinkle-related disorders.
• To define the spectrum and progression patterns of Twinkle-related disorders.
• To identify mutational hotspots and their clinical relevance.

Main Methods:

• Retrospective cohort study of 189 patients across multiple international centers.
• Data collection from medical records, including clinical features, onset age, and genetic testing.
• Phenotypic categorization and analysis of TWNK variants.

Main Results:

• Primary mitochondrial myopathy (PMM) was the predominant syndrome (85.2%).
• Progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%) were common.
• 73 TWNK variants, including 16 novel ones, were identified, often in critical functional regions.

Conclusions:

• This study expands the understanding of Twinkle-related disorders' phenotypic and genotypic spectrum.
• Identified mutational hotspots correlate with clinical relevance.
• International collaborations like TReDIC are vital for rare disease research and clinical trial design.