To report an adult with chronic progressive external ophthalmoplegia (CPEO), myopathy, neuropathy, and parkinsonism carrying a novel TWNK helicase-domain variant, expanding the phenotypic spectrum of TWNK-related disease.

TWNK encodes the Twinkle mitochondrial DNA helicase, essential for mitochondrial DNA maintenance. Pathogenic variants typically cause autosomal dominant progressive external ophthalmoplegia, sometimes with multisystem involvement. The spectrum of TWNK-associated manifestations remains incompletely defined.

Genomic exome sequence analysis was performed using a hybridization-based protocol, and sequenced using Illumina technology.

A middle-aged man of Russian Jewish ancestry had bilateral ptosis and progressive ophthalmoplegia for approximately 20 years, without diurnal fluctuation. Examination showed bilateral ptosis, restricted extraocular movements in all directions, bilateral proximal limb weakness, a resting tremor and bradykinesia.  Nerve conduction studies showed absent sural and superficial peroneal sensory responses on the right, mildly reduced velocities in the right tibial nerve, with otherwise preserved upper-limb studies; EMG demonstrated a myopathic pattern in facial and proximal muscles and mild chronic distal neurogenic changes in the distal extremities bilaterally. Sequence analysis showed TWNK Exon 2,  c.1453T>A (p.Phe485Ile), heterozygous, in TWNK, within the helicase-domain hotspot; The patient’s father had long-standing ptosis, ophthalmoplegia, sensorimotor neuropathy, bradykinetic features on exam, myopathic patterns on EMG, and a muscle biopsy concerning for a mitochondrial myopathy. The patient's paternal grandfather, paternal uncle and paternal first cousin all had similar neuromuscular/ophthalmologic phenotypes.

This case expands the TWNK spectrum to include a combined CPEO–myopathy–neuropathy phenotype with clinically significant parkinsonism in an adult and highlights a novel helicase-domain variant that is absent from the literature.