A case report presented at the 2026 American Academy of Neurology annual meeting in Chicago describes a 63-year-old man with a novel variant in the TWNK gene who experienced chronic progressive external ophthalmoplegia (CPEO, a condition that weakens the eye muscles), myopathy, neuropathy and parkinsonism.
TWNK-associated disease comprises a group of mitochondrial disorders that may produce symptoms similar to those of thymidine kinase 2 deficiency (TK2d). These conditions are also known as Twinkle-related disorders.
The patient, who had Russian Jewish ancestry, presented with a 20-year history of upper eyelid drooping and progressive eye muscle weakness. Upon examination, he was unable to move his eyes in any direction. He also displayed tremors, limb weakness and slowness of movement.
Nerve conduction studies showed abnormal nerve function in his right leg and foot, with no notable upper limb findings. Furthermore, electromyography demonstrated signs of muscle disease in the face and proximal muscles.
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The patient then underwent genetic testing, which revealed a mutation in exon 2 of the TWNK gene. Specifically, at position 485 of the protein, phenylalanine was replaced by isoleucine. Only one of the two copies of the gene carried this variant.
This mutation is located in the helicase-domain hotspot, an area of the protein key for mitochondrial DNA replication and repair. This variant has not previously been reported in research about the disease.
The individual’s father exhibited very similar symptoms on clinical examination, including drooping eyelids and eye weakness. Electromyography and muscle biopsy further suggested mitochondrial myopathy in the father.
“The patient’s paternal grandfather, paternal uncle and paternal first cousin all had similar neuromuscular/ophthalmologic phenotypes,” the authors added.
This case study widens the scope of Twinkle-related diseases to include a unique phenotype defined by a combination of CPEO, myopathy and neuropathy. Because of its notable overlap with TK2D, awareness of the spectrum of symptoms observed across both diseases may facilitate timely diagnosis.
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