Objective: To characterize speech and voice dysfunctions in ATP1A3 mutation positive individuals compared to concurrent mutation negative family controls.

Background: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP), which is caused by ATP1A3 mutations1-3. Though previous studies have noted these symptoms, speech and voice dysfunction in these patients has not been formally characterized or quantified.

Method: Voice recordings were analyzed in 32 subjects with ATP1A3 mutations (male=21, female=11) and 29 mutation negative family controls (male=15, female=14) from families having at least one RDP patient, i.e. ATP1A3 positive with movement disorder onset after 18 months of age. Three raters (1 fellowship-trained laryngologist and 2 speech/language pathologists) evaluated the audio to determine voice quality and presence of dysarthria. Raters were blinded to mutation status reviewed audio in randomized order. Dysarthria was classified by subtype. The Grade, Roughness, Breathiness, Asthenia, Strain (GRBAS) scale was used to rate voice quality. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) total scores were used to assess overall dystonia. P< 0.05 denoted statistical significance.

Results: Out of the 32 subjects with a positive ATP1A3 mutation status, 23 had dysarthria and 9 had no perceptible neurological voice condition. Of the 29 ATP1A3 mutation negative controls, 5 had dysarthria and 24 had no perceptible neurological voice condition. Positive mutation status was associated with dysarthria (p< 0.0001). Subjects with positive ATP1A3 mutation status and dysarthria had subtypes as follows: 3 hyperkinetic, 5 hypokinetic, 5 flaccid, 3 ataxic and 7 with ≥2 subtypes. There was a significant difference between mutation positive and negative subjects with respect to Grade (p< 0.0001), Roughness (p=0.005), Asthenia (p=0.015) and Strain (p=0.0003). There were positive correlations between BFMDRS scores and Grade, Breathiness and Asthenia scores (r=0.19, r=0.22, r=0.22) though not significant.

Conclusion: Voice and speech analysis are an important part of assessing patients with ATP1A3 mutations as they frequently experience dysarthria and impairment in the Grade, Roughness, Asthenia and Strain of their voices. Future directions include utilizing bulbar-specific dystonia assessments and examining correlates to BFMDRS bulbar dystonia symptoms.

References: 1Dobyns, W. B., Ozelius, L. J., Kramer, P. L., Brashear, A., Farlow, M. R., Perry, T. R., … Breakefield, X. O. (1993). Rapid-onset dystonia-parkinsonism. Neurology, 43(12), 2596–2602. 2Kramer, P. L., Mineta, M., Klein, C., Schilling, K., De Leon, D., Farlow, M. R., … Brashear, A. (1999). Rapid-onset dystonia-parkinsonism: Linkage to chromosome 19q13. Annals of Neurology, 46(2), 176–182. 3Brashear, A., Dobyns, W. B., de Carvalho Aguiar, P., Borg, M., Frijns, C. J. M., Gollamudi, S., … Ozelius, L. J. (2007). The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain, 130(3), 828–835.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/auditory-perceptual-voice-and-speech-evaluation-in-atp1a3-positive-patients/