To describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism from a Twinkle mutation.
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.
Members of a 3-generation family followed up in a neuromuscular disease center for dominantly inherited progressive external ophthalmoplegia.
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.
This finding broadens the clinical spectrum of Twinkle gene mutations and further implicates loss of mitochondrial DNA integrity in the pathogenesis of Parkinson disease.