Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle

Objective: To describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism from a Twinkle mutation. Design: All coding exons of POLG1, Twinkle ( aka C10ORF2, PEO1), and ANT1 ( SLC25A4) were sequenced in the proband with targeted sequencing of the Twinkle gene in all additional subjects. Subjects: Members of a 3-generation family followed up in a neuromuscular disease center for dominantly inherited progressive external ophthalmoplegia. Results: We identified a heterozygous G1121A mutation ( R374Q) in exon 1 of Twinkle that segregated with the disease phenotype in all affected family members. No pathogenic mutations were present in POLG1 or ANT1. Conclusion: This finding broadens the clinical spectrum of Twinkle gene mutations and further implicates loss of mitochondrial DNA integrity in the pathogenesis of Parkinson disease.