Objective: To describe a rare manifestation of Twinkle gene mutation causing not only progressive external ophthalmoplegia (PEO), but also parkinsonism.

Background: PEO is one of the most common clinical manifestations of mitochondrial disease and its most frequent cause is mitochondrial DNA (mtDNA) single deletions. Twinkle gene (TWNK) mutation is responsible for autosomal dominant PEO. However, its mutation causing not only PEO, but also Parkinsonism have been rarely described.

Method: A 68 year old man with a previous history of systemic arterial hypertension, high risk for diabetes and depression sought neurological care complaining of tremor that worsens with physical exertion since the age of 65, with slow and progressive worsening since then. At the same time, he also began to experience erectile dysfunction, progressive hypophonia and slowness of movements. Clinical examination reviewed bilateral ptosis with restriction of eye movements in all gaze directions compatible with PEO. When asked, the patient confirmed diplopia and a positive family history of eyelid ptosis (sister, father, cousins and five paternal uncles). Several family members also present diabetes mellitus even without PEO. The tremor was postural and kinetic, bilateral both grade 1 (worse in the left hand). There was no resting tremor. He also showed grade 2 bradykinesia and grade 2 rigidity only in the left upper limb. He had a gait with reduced swinging of the arms, specially at the left arm. The Pull test was negative. The rest of the neurological examination was unremarkable. There were no complaints of constipation, olfactory changes, sleep disorders, deafness, cognitive issues, nor signs of peripheral neuropathy.

Results: General laboratory tests, EMG and magnetic resonance image were unremarkable. Brain scintigraphy with TRODAT-99mtc evidenced an asymmetric dopaminergic hypoactivity in the striatum, greater on the right side. Whole exome and mitochondrial DNA sequencing identified a heterozygous pathogenic variant – c.1075G>A:p. (Ala359Thr) – in the exon 1 of TWNK gene, characterized by multiple mtDNA deletions of autosomal dominant inheritance.

Conclusion: There are few reports in the literature which describe parkinsonism due to TWNK mutation, generally described as mild, associated with nigrostriatal reduction uptake and responsiveness to levodopa as in the idiopathic PD, even with levodopa induced dyskinesias and motor fluctuations.

References: [1] Hirano M, Pitceathly RDS. Progressive external ophthalmoplegia. Handb Clin Neurol. 2023;194:9-21. doi: 10.1016/B978-0-12-821751-1.00018-X. PMID: 36813323; PMCID: PMC10440731.Neurosci Lett. 2013 Nov 27;556:1-4. doi: 10.1016/j.neulet.2013.09.034. Epub 2013 Sep 26. PMID: 24076137.

[2] Kiferle L, Orsucci D, Mancuso M, Lo Gerfo A, Petrozzi L, Siciliano G, Ceravolo R, Bonuccelli U. Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsonism-associated-with-twinkle-gene-mutation/