Sleep problems and fatigue appear to be comorbidities of Usher syndrome type 2A (USH2A) not, as previously thought, consequences of the condition’s hearing impairment and vision loss, Erwin van Wijk, PhD, and colleagues report in Ophthalmology Science.
“This study demonstrates a high prevalence of fatigue and poor sleep quality experienced by patients with USH2A,” they wrote. “The absence of a relationship between the level of visual impairment and the severity of reported sleep problems suggests a different origin of sleep problems in the USH2A population than for the general blind community.”
Usher syndrome’s estimated global prevalence is 1 in 20,000, amounting to 400,000 patients worldwide, and it is responsible for around 50% of all people with hereditary deaf-blindness. Four clinical types vary by the age of onset of retinitis pigmentosa, the onset, severity, and progression of hearing impairment, and the presence or absence of vestibular dysfunction.
Roughly two-thirds of all patients with Usher syndrome have type 2, with moderate to severe congenital hearing impairment and retinitis pigmentosa presenting around puberty or in early adulthood. Of these, up to 85% can have USH2A due to pathogenic variants in the USH2A gene.
Poor Sleep Quality Indicative of USH2A
“Poor sleep quality is a hallmark symptom of USH2A, yet no reports on poor sleep quality with the syndrome exist in the literature,” Dr. van Wijk notes. He and his research team conducted a cross-sectional study in 56 genetically confirmed adult Dutch patients with USH2A (roughly 15% of Dutch patients with USH2A) and in 120 adult healthy controls. In both groups, participants were, on average, in their early 40s.
The researchers assessed sleep quality and prevalence as well as sleep disorder type, chronotype, fatigue, and daytime sleepiness using 5 questionnaires: 1.) Pittsburgh Sleep Quality Index (PSQI), 2.) Holland Sleep Disorders Questionnaire (HSDQ), 3.) Morningness-Eveningness Questionnaire (MEQ), 4.) Checklist Individual Strength (CIS), and 5.) Epworth Sleepiness Scale (ESS). For a subset of patients, they used recent visual function data to study the potential correlation between questionnaire results and disease progression. They used these questionnaires to compare the results of controls with patients with USH2A. The study team then evaluated the scores of the patients with disease progression according to age, visual field size, and visual acuity. They analyzed data using the Wilcoxon rank-sum test.
The authors found:
1 On the PSQI, patients with USH2A experienced poorer sleep quality when compared with controls (P<0.001). Patients with USH2A went to bed slightly earlier and got out of bed slightly later, so their time in bed was significantly higher (P=0.003). And because they spent more time in bed but slept the same number of hours as those in the control group, their sleep efficiency compared with controls was lower (P=0.010).
2 Respondents to the HSDQ with USH2A were more likely to have sleep disorders—including insomnia, hypersomnia, parasomnia, sleep-related movement disorders, and circadian rhythm sleepwake disorder—when compared with controls (P<0.001).
3 Both groups had similar chronotype (tendency to wake up early and be more active in the morning vs be more active in the evening and sleep late) on the MEQ. Most participants were “intermediate,” defined as neither early risers nor late sleepers.
4 Patients with USH2A were significantly more likely than controls to report fatigue (P<0.001) on the CIS.
5 On the ESS, patients with USH2A were significantly more likely than controls to report daytime sleepiness (P<0.001).
Sleep Problems and Fatigue Appear Before Vision Loss
The study team found no significant correlation found between visual acuity and PSQI, HSDQ, or CIS scores. However, the team did find a small correlation with low strength (R2=0.14) between visual acuity and ESS score (linear regression line P=0.045).
“The sleep disturbances and high levels of fatigue were not correlated with the level of visual impairment,” the authors write. “These results are in accordance with the patients’ experiences that their sleep problems already existed before the onset of vision loss.”
“Parents note that their children with USH2A have poor, irregular sleep quality long before their first clinical signs of visual dysfunction, and that poor sleep quality is the biggest problem they deal with,” Dr. van Wijk explains. “Because light perception has a direct role in regulating circadian rhythm and sleep, this suggests a direct problem related to the absence (or dysfunction) of usherin, the protein encoded by the USH2A gene, rather than the result of a double sensory deficit.”
“In addition to an otolaryngologist and an ophthalmologist, the USH2A patient’s multidisciplinary care team should include a somnologist to monitor their sleep quality,” he advises.
The researchers plan to investigate whether poor sleep quality is also a feature of the other three Usher syndrome subtypes or related disorders. They are also analyzing the components of sleep for patients with USH2A and are exploring whether an underlying molecular mechanism may cause sleep disturbances. They hope this knowledge may lead to personalized melatonin treatment, sleep training, or both.
