Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency

Area of Science:

• Neurology
• Genetics
• Mitochondrial Diseases

Background:

• Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy.
• Late-onset TK2d presentations are poorly understood, lacking defined natural history.
• This study focuses on characterizing the progression of late-onset TK2d in untreated patients.

Purpose of the Study:

• To prospectively investigate the natural history of late-onset Thymidine kinase 2 deficiency (TK2d).
• To identify and quantify clinical outcomes for future therapeutic trial design.
• To provide insights into the progression of this underrepresented mitochondrial myopathy.

Main Methods:

• A prospective, single-centre natural history study.
• Involved 11 untreated patients with late-onset TK2d over 24 months.
• Utilized clinical assessments, muscle biopsies, MRI, and serum biomarker analysis (GDF15).

Main Results:

• Median age at onset was 27.2 years; phenotypes included myopathy, ophthalmoplegia, and exercise intolerance.
• Most patients required ventilation (72%) and had axonal polyneuropathy (70%).
• Significant clinical deterioration observed over 2 years, with declines in NSAA, FVC, and 100m run times; GDF15 correlated with function.

Conclusions:

• This study provides the first prospective longitudinal characterization of late-onset TK2d.
• Identified quantifiable outcomes (e.g., NSAA, FVC, GDF15) relevant for future clinical trials.
• Findings are crucial for designing trials in TK2d and other mitochondrial myopathies.