TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Mitochondrial Diseases

Background:

• Biallelic thymidine phosphorylase (TYMP) variants cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a severe, juvenile-onset disorder.
• A milder, late-onset form of MNGIE is rarely documented, presenting diagnostic challenges.

Purpose of the Study:

• To investigate the role of TYMP gene defects in adult patients presenting with muscle mitochondrial DNA (mtDNA) instability.
• To identify potential genetic causes for late-onset MNGIE or related phenotypes.

Main Methods:

• Gene panel sequencing was performed on a cohort of 60 patients with muscle mtDNA deletions.
• Biochemical and molecular analyses were conducted to confirm TYMP variant pathogenicity.

Main Results:

• TYMP defects were identified in 5% (3/60) of patients with muscle mtDNA instability.
• Two of these patients exhibited late-onset symptoms (onset >40 years), with one presenting solely with ptosis and ophthalmoparesis.
• Genetic and biochemical findings confirmed TYMP deficiency as the cause of disease in these individuals.

Conclusions:

• TYMP gene screening is crucial for adult patients with unexplained muscle mtDNA instability, even in the absence of typical MNGIE symptoms.
• This highlights the potential for TYMP variants to cause milder, late-onset neurological and ophthalmological manifestations.