Finding Twinkle in the Eyes of a 71-Year-Old Lady: A Case Report and Review of the Genotypic and Phenotypic Spectrum of TWINKLE-Related Dominant Disease

Progressive external ophthalmoplegia (PEO) call be caused by a disorder characterized by multiple mitochondrial DNA (mtDNA) deletions due to mutations in the TWINKLE gene, encoding a mtDNA helicase. We describe a 71-year-old woman who had developed PEO at age 55 years. She had cataracts, diabetes, paresthesias, cognitive defects, memory problems, hearing loss, and sensory ataxia. She had muscle weakness with ragged red fibers oil biopsy. MRI showed static white matter changes. A c.908G > A substitution (p.R303Q) in the TWINKLE gene was identified. Multiple mtDNA deletions were detected ill muscle but not blood by a PCR-based method, but not by Southern blot analysis. MtDNA copy number was maintained ill blood and muscle. A systematic literature search was used to identify the genotypic and phenotypic spectrum of dominant disease. Patients were adults with PEO and symptoms including myopathy, neuropathy, dysarthria or dysphagia, sensory ataxia, and parkinsonism. Diabetes, cataract, memory loss, hearing loss, and cardiac problems were infrequent. All reported mutations clustered between amino acids 303 and 508 with no mutations at the N-terminal half of the gene. The TWINKLE gene should be analyzed in adults with PEO even in the absence of mtDNA deletions in muscle oil Southern blot analysis, and of a family history for PEO. The pathogenic mutations identified 5' beyond the linker region suggest a functional role for this part of the protein despite the absence of a primase function in humans. In our patient,the pathogenesis involved multiple mtDNA deletions without reduction in mtDNA copy number. (c) 2009 Wiley-Liss, hic.