Establishing a natural history of X-linked dystonia parkinsonism

Abstract

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the <i>TAF1</i> gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.