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Williams syndrome and hyperacusis.

See also: Congenital hearing loss

Timothy C. Hain, MD of Chicago Dizziness and Hearing.

Last updated: May 8, 2019

Williams syndrome (WS) is an extensively studied genetic disorder which includes hyperacusis. It affects about 1/10,000 people. It is a consequence of hemideletion of about 2 dozen genes in chromosome 7, that code for elastin (Benitez-Burraco and Kimura, 2019; Twitte et al, 2019). Although autosomal dominant, most cases are de-novo. The main symptom is borderline intelligence (Sauna-Aho et al, 2019). This is accompanied by hypersociability (Barak et al). Congenital heart disease is also common and this is the leading cause of morbidity and mortality in these patients (Collins, 2018). There may be a small head, a shortened posterior cranial base, and thick calvarial bones (Matsuno et al, 2018). This is sometimes called an "elfin" face. (Maurino et al, 2017). Some have persistent hypercalcemia and vitamin D is often to be avoided.

The brain in Williams syndrome is wired differently, with hyperconnectivity of the posterior regions and reduced connectivity of anterior regions. (Gagliardi et al, 2018). William's patients are generally very good at recognizing faces and emotions (Ibernon et al, 2018).

According to Canales et al (2015), "Our results show that Gtf2ird1 is expressed in a number of cell types within the cochlea, and Gtf2ird1 null mice showed higher auditory thresholds (hypoacusis) in both ABR and DPOAE hearing assessments. These data indicate that the principal hearing deficit in the mice can be traced to impairments in the amplification process mediated by the outer hair cells and suggests that similar mechanisms may underpin the SNHL experienced by WBS patients. " As WS patients mainly seem to have phonophobia rather than much in the way of hearing impairment, this study may be explaining something that is not very troublesome to WS patients.

Hearing related literature and Williams syndrome.

Cochlear function:

Barrozzi et al (2012) reported on audiological findings "Although hearing loss does not seem to be frequent, a cochlear fragility, especially in the high frequency range, related to outer hair cells is characteristic of WS." Or in other words, the outer hair cells tend to die earlier than in normal persons. This might suggest that hearing protection is more important in WS patients than the general population.

Attias et al (2008), reported that "The medial olivocochlear (MOC) efferent system was tested by stimulation of the contralateral ear with increasing levels of white noise, while recording transient evoked otoacoustic emissions (TEOAE) in the ipsilateral ear. The suppression effect on the amplitudes of the TEOAE was computed for each contralateral stimulus level. This measure reflects the strength of the MOC efferent system. In addition, the thresholds of ipsilateral and contralateral acoustic reflexes in response to 1, 2 and 4 kHz tones as well as to broadband stimuli were also recorded. Results showed that patients with WS had a significantly higher suppression effect of the MOC reflex on TEOAE. Ipsilateral and contralateral acoustic reflexes to tonal and broadband stimuli presented at maximum stimulus intensities were absent in 62-86% of the patients with WS. In the remainder, acoustic reflexes were elicited at lower auditory sensation thresholds than in controls. Hyperexcitability of the MOC efferent system coupled with absence of acoustic reflexes may contribute to the hyperacusis in WS and the consequent high-tone hearing loss induced by environmental noise. Both measures can be used for objective detection and thus, intervention of hyperacusis in the early stages of life." This is a bit confusing. The higher effect of the suppression would suggest better function in WS patients. The loss of acoustic reflexes, suggests worsened function.

Johnson et al (2001) also supported the idea that there may be a vulnerable cochlea in WS. They conluded: "Three patients had high-frequency sensorineural hearing loss (SNHL) and thus, as expected, absent TEOAEs, indicating cochlear damage. Two had normal hearing and normal TEOAEs. However, four patients had normal hearing with absent TEOAEs. CONCLUSIONS: These findings are suggestive of cochlear disease and may, in fact, support the hypothesis of outer hair cell modulation by the ipsilateral medial olivocochlear system. Behavioural aspects of the syndrome make audiologic testing difficult. Thus, the diagnosis of SNHL may be hampered if it truly exists. The data show a preponderance of SNHL in the older age groups of our study population. This either reflects previously missed diagnoses or underlying cochlear disease, which may manifest later in life. Thus, this finding blurs the boundary between loudness recruitment and hyperacusis."

Marler et al (2005, 2010) also pointed out that DPOEs tended to be low. They noted: " In the objective DPOAE testing, 19/25 (76%) had DPOAE absolute amplitudes below the 5th percentile for ears with normal hearing [Gorga et al. (1997); Ear Hear 18(6):440-455]. We report SNHL in 14/18 (78%) of school-age children with WS. Post hoc analyses revealed a significant effect for age, suggesting a pattern of progressive hearing loss. An effect size analysis indicated a clinically meaningful difference in the hearing sensitivity between school-aged children and adults in the high frequencies (4,000 and 8,000 Hz). Similar hearing loss phenotype was observed in patients with familial nonsyndromic supravalvular aortic stenosis (SVAS), suggesting that molecular defects in the elastin gene in the pathogenesis of SNHL in WS. "

Paglialonga et al (2011, 2014) pointed out the importance of using OAE's in WS.

 

Phonophobia/Hyperacusis

According to Van Borsel et al (1997), hyperacusis was reported in 95% of WS patients.

According to Dror et al (2018), "Phonophobia and ADHD are the most prevalent psychiatric diagnoses in people with WS. Phonophobia was significantly associated with the risk for ADHD in WS participants. " Anxiety is 4 times more prevalent than in the normal population controlled for intellectual disability (Royston, 2017).

Silva et al (2018) reviewed the auditory characteristics of persons with William's syndrome. They reported (from 12 studies) "It was possible to observe prevalence of type A tympanometry curve, which may occur with absence of acoustic reflexes, mild to moderate sensorineural hearing loss, affecting mainly the high frequencies, absent or less amplified otoacoustic emissions, and brainstem auditory evoked potential without retrocochlear alteration. "

Gotelf et al (2006) discussed hyperacusis in WS. They concluded: Forty-one of the 49 children with WS (84%) had hyperacusis of moderate to severe degree, which began in infancy. Of these, 21 (mean age 15.8 +/- 5.5 years) were quantitatively tested. Subjects with WS reported discomfort at sound intensities on average 20 dB lower than control subjects. Pure-tone audiometry and distortion products otoacoustic emission test revealed a high-frequency cochlear hearing loss. An absence of ipsilateral acoustic reflex responses to maximum stimulation was significantly more common in the subjects with WS than controls. On BAER testing, the WS group had a significant prolongation in wave I latency. CONCLUSIONS: Hyperacusis in Williams syndrome (WS) is associated with a high-frequency hearing loss resembling the configuration of noise-induced hearing loss. The hyperacusis and hearing loss in WS may stem from a deficiency in the acoustic reflex resulting from auditory nerve dysfunction. Additional mechanisms that may mediate hyperacusis in WS and should be evaluated in future studies include recruitment, malformation of the facial canal, and haploinsufficiency of the elastin gene. " This suggests that hyperacusis in WS is similar to hyperacusis in persons who have injured their ears from loud noise.

Matsumoto et al (2011) suggested that there was abnormal OHC function, which results in hyperacusis and progressive hearing loss in WS.

Miani et al (2001) recommended "acoustic training" for treatment.

Nigam and Samuel (1994), reported that a case of WS was very sensitivity to insertion of a grommet in the ear drum.

 

Central integration

D'Sousa et al (2016) noted "Infants with Williams syndrome failed to demonstrate a McGurk effect, indicating poor AV speech integration".

Jacobs et al (2018) reported that there were attentional processes that distinguish WS from normal subjects. " Individuals with Williams Syndrome (WS) exhibit an atypical auditory profile. Across two experiments, we used event-related potentials (ERPs) in a three-stimulus auditory oddball task to examine early sensory (P1, N1, P2) and later cognitive (P3a, P3b) stages of cortical auditory processing in adults with WS and age-matched typical peers. In Study 1, piano chords served as standard, target, and novel stimuli; whereas, in Study 2, a variety of non-piano sounds comprised the novel stimuli. Across both experiments, there were no group differences in the earliest stages of sensory encoding (P1, N1), along with evidence for atypically large P2 responses in participants with WS. Persons with WS exhibited larger than typical P3a responses when the novel stimuli were perceptually distinct from the standard and the target stimuli (Study 2), but not when task-relevant and -irrelevant stimuli were perceptually similar (Study 1). Further, the WS group demonstrated reduced goal-directed attention (attenuated P3b response). These group differences in ERPs were not directly related to IQ. Our results in the context of an active discrimination task point to a more complex profile of auditory processing in persons with WS than previously reported, with group differences emerging during the later stages of stimulus categorization and evaluation, but not within early stimulus detection and feature encoding." We find this difficult to decode.

Levitan et al (2003) performed FMRI (which is a rather noisy procedure), and reported "Those regions supporting music and noise processing in normal subjects were found not to be consistently activated in the WS participants (e.g., superior temporal and middle temporal gyri). Instead, the WS participants showed significantly reduced activation in the temporal lobes coupled with significantly greater activation in the right amygdala. In addition, WS participants (but not controls) showed a widely distributed network of activation in cortical and subcortical structures, including the brain stem, during music processing. Taken together with previous ERP and cytoarchitectonic studies, this first published report of WS using fMRI provides additional evidence of a different neurofunctional organization in WS people than normal people, which may help to explain their atypical reactions to sound. " This would support a central explanation for at least some of the auditory abnormalities in WS.

Levitan et al (2005), reported "A frequent characteristic of the phenotype is adverse reactions to, and/or fascination with, certain sounds. Previously published reports indicate that people with WS experience hyperacusis, yet careful examination reveals that the term 'hyperacusis' has been used indiscriminately in the literature to describe quite different auditory abnormalities. METHOD: In an effort to clarify and document the incidence of auditory abnormalities in and among people with WS we collected data from parents of people with WS (n = 118) and comparison groups of people with Down syndrome, autism, and normal controls. RESULTS: Our findings revealed four phenomenologically separate auditory abnormalities, all of which were significantly more prevalent in WS than the three comparison groups." We also find this difficult to decode.

Summary:

Williams syndrome (WS)is a genetic disorder that has, among other symptoms, hyperacusis (phonophobia), anxiety, and abnormal cortical organization. Hyperacusis, in the sense that sounds that do not bother other people, annoy these patients is exceedingly common in WS. There are relatively mild abnormalities in the inner ear, that may make these patients more sensitive as well as cause eventual hearing decline. There are also substantial changes in cortical organization, which provide a second potential explanation. These patients are also often anxious.

This is a not a very satisfying situation - -the problem is either in the ear or in the brain. Well what does that tell us ?

There appear to be no treatment studies of hyperacusis in WS patients -- no trials of medications are reported. This is likely because WS is rare. With respect to the inner ear issue - - which appears to involve the outer hair cells, it would seem prudent to avoid NSAID/aspirin type drugs as these are all outer hair cell toxins. There are currently no drugs that are thought to preserve outer hair cells from damage. Whether or not use of ear plugs or ear protection is especially useful in WS patients is unexplored. One would think that it would be helpful, given that the problem is peripheral as some research suggests.

Regarding the central organization hypothesis, medications usually affect the entire brain, and are not well suited to selective modulation of cortical organization. TMS might eventually be a tried.

Regarding the anxiety that WS patients have demonstrated in studies, this likely increases the fear factor portion of hyperacusis/phonophobia. Medications that reduce anxiety are likely to be helpful. These might include mood stabilizers, antidepressants, benzodiazepines, or atypical drugs for anxiety.

References:

 

 
Copyright May 8, 2019 , Timothy C. Hain, M.D. All rights reserved. Last saved on May 8, 2019