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 TAF1 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.

Keywords: X-linked; dystonia; natural history; parkinsonism.

Graphical Abstract

Figure 1

Age of onset. Reported age of onset (provided by the subject) versus estimated age of onset (inferred by the model). Data shown for symptomatic gene-positive males (n = 29).

Figure 2

Model-based summary of progression versus age. The points show the progression summary value at each visit for each participant, and the thin lines show the estimated piecewise linear trajectory for each participant as a function of age. Data shown for all gene-positive males (n = 29 symptomatic, n = 7 pre-symptomatic).

Figure 3

Participant weight versus the progression summary. Successive timepoints for the same participant are connected by lines. Data shown for gene-positive males (n = 29 symptomatic, n = 7 pre-symptomatic). For A, B, C, these are estimates based on the symptom trajectory model; no statistical testing involved.

Figure 4

Estimated rates of progression. Estimated rates of progression for each pre-defined category, for each symptomatic gene-positive subject, except for subject 14D. Subjects are ordered (highest to lowest) according to their average rate across the 13 categories. Estimates based on the rate heterogeneity analysis; no statistical testing involved.