Adult-onset leg dystonia due to a missense mutation in THAP1.

THAP1 encodes a transcription factor that contains an atypical zinc finger domain and regulates cell proliferation in the context of cell cycle progression.1 An Exon 2 insertion/deletion frameshift mutation in THAP 1 produces DYT 6 dystonia in Amish-Mennonites.1 Two early, follow-up studies identified 11 additional sequence variants in familial, primarily early-onset, primary dystonia.2 More recently, a heterogeneous collection of THAP1 sequence variants has been associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia. Adult-onset dystonia characteristically begins in the craniocervical or brachial areas and tends to remain confined to these regions, whereas dystonia manifesting before the age of 30 usually starts in a leg or arm and then becomes more generalized.3 Peripheral trauma and other sensorimotor perturbations may induce dystonia in genetically predisposed individuals.4,5 Adult-onset focal lower extremity dystonia usually involves foot inversion.6 A 63-year-old, right-handed American man of Danish ancestry, and without known Amish-Mennonite roots, presented with a 12-year history of gait difficulties, initially manifesting as intermittent “flopping” of his left foot and paresthesias over the lateral aspect of his left leg. He had not undergone lumbo-sacral spine surgery. Over time, the patient began to notice that his left leg would feel “tight, like a bow” while ambulating. He also found that he would “need to walk quicker to feel more stable.” Indeed, his wife has noticed that he seems to walk at a “double-step” now. He has not found other gait adaptations that will alleviate his problem nor is a diurnal variation apparent; the feeling of “tightness” in his leg is only apparent while ambulating. A couple of years before presentation, the patient retired from the post office, because of deterioration in his handwriting, associated with “shaking” and a feeling of “tightness” in his forearm and hand. The latter has not been alleviated by alcohol consumption or writing in different positions. The patient does not have much difficulty with tasks, such as eating, pouring, or dressing. His deceased father was diagnosed with “torticollis” after sustaining a neck injury at age 16, and a living, paternal aunt developed “neck shaking and twitching,” allegedly after undergoing thyroid surgery in her 20s. The patient’s examination was notable for mild, left L5/S1 distribution weakness. His gait revealed excessive contraction of his left hamstrings and gastrocnemius as he made a step with his left leg; having him walk backward and run did not alleviate his gait dysfunction notably (see video, segment 1). The patient had a severe writing tremor, yet only a subtle postural and action upper limb tremor, and no action tremor on pouring (see video, segments 2 and 3), suggesting that his writing tremor is likely dystonic. No adventitial neck movements or abnormal cervical or upper limb postures were evident. Electromyography revealed evidence of a relatively mild, quiescent, left L5/S1 radiculopathy. Sequencing of THAP1 in the forward and reverse directions revealed a c.446T>C sequence variant, producing substitution of a strongly hydrophobic isoleucine residue with a threonine (l149T) in the nuclear localization signal domain of THAP1. The patient’s paternal aunt, alluded to above, was found to harbor the same c.446T>C sequence variant. The patient has not responded to a levodopa trial and has not been interested in pursuing other treatment options, such as botulinum toxin injections. Our patient’s history of present illness, family history, neurologic and neurophysiologic examinations, and THAP1 mutation demonstrate that adult-onset, primary dystonia may begin in a lower extremity, may not be associated with foot inversion, and reinforces that the anatomic site of onset of a primary dystonia may be influenced by trauma and/or a structural lesion, potentially producing a multifocal dystonic state.