Quantitative Analysis of Phonatory Dysfunction in Female FMR1 Premutation Carriers as a Potential Biomarker of Preclinical Fragile X-Associated Tremor/Ataxia Syndrome Symptoms

Meagan Lauber


While fragile X syndrome occurs in individuals possessing >200 CGG repeats on the FMR1 gene, those possessing 55-200 repeats are classified as FMR1 premutation carriers. Previously, FMR1 premutation carriers were believed to be unaffected; however, research now shows they display distinct phenotypes, with a large concern being their risk of developing fragile-X-associated tremor/ataxia syndrome (FXTAS) as they age. FXTAS is a neurodegenerative disorder characterized by tremors, parkinsonism, cerebellar-gait ataxia, brain atrophy, and neuropathy. Given that the premutation effects 1 in 148 women and 1 in 290 men and the inability to reliably predict which carriers will develop FXTAS later in life, it is necessary to develop methods of identifying potential pre-clinical FXTAS symptoms that are accessible to medical professionals. Phonation is the production of speech via modulation of laryngeal tension to allow airflow that causes the vocal cords to vibrate. The neuromuscular sensitivity of the phonatory system makes it an ideal bodily system for detecting subtle neuropathologies that may occur before the onset of noticeable symptoms. Sustained /a/ phonation samples were obtained from 21 FMR1 premutation carriers and 28 neurotypical controls and were run through Praat Linguistic Analysis software to calculate key phonatory parameters: mean and standard deviation of fundamental frequency (F0) , number and degree of voice breaks, noise-to-harmonics ratio (NHR) and harmonics-to-noise-ratio (HNR). Results showed significant differences in standard deviation of F0 and NHR between the premutation and control groups. Results also showed that 57% of FMR1-premutation carriers met pathology thresholds for either NHR or HNR, with 33% meeting both, compared to the control group where 14% met one and 7% met both. Additionally, key vocal parameters were associated with indices of health, motor functioning, and balance performance. These results supports the merit of phonatory parameters as a potential biomarker of subtle neuromuscular degeneration that could be used as an early diagnostic tool of pre-clinical FXTAS symptoms.