A Retrospective Study of Hearing Loss in Patients Diagnosed with Peroxisome Biogenesis Disorders in the Zellweger Spectrum

Abstract

Objectives: Peroxisome Biogenesis Disorders in the Zellweger Spectrum (PBD-ZSD) are autosomal recessive disorders characterized by defects in peroxisome function, biosynthesis, and/or assembly. Despite its frequent documentation, hearing loss associated with PBD-ZSD has not been extensively characterized. The purpose of this retrospective natural history study was to better characterize the hearing loss associated with PBD-ZSD and to provide additional insight into the evaluation and management of PBD-ZSD patients with hearing loss.

Design: Audiological data from medical records of 42 patients with PBD-ZSD or D-bifunctional protein deficiency were collected from an ongoing longitudinal retrospective natural history study. An initial dataset of 300 audiograms and/or audiometric test results from the 42 patients were used to characterize the degree of hearing loss, type of hearing loss, relationships between air and bone conduction thresholds, age-related changes in hearing loss, and benefit with amplification.

Results: The majority of PBD-ZSD patients in this study presented with moderately-severe to severe hearing loss and relatively slow rates of longitudinal changes in hearing sensitivity. Improvements in hearing thresholds were observed with use of hearing aid amplification. Though bone conduction data were limited, air-bone gaps and air conduction threshold fluctuations observed in several patients suggest there may be an increased occurrence of mixed hearing losses in PBD-ZSD populations.

Conclusion: The results of this retrospective study provide insight into the hearing loss associated with PBD-ZSD, but also emphasize the need for more complete assessments of hearing loss type and middle ear function in these patients. The addition of more comprehensive datasets to the ongoing natural history study will enhance our understanding of the pathophysiology underlying PBD-ZSD and guide the development of targeted evaluation and management recommendations for patients with PBD-ZSD.

Trial registration: ClinicalTrials.gov NCT01668186.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1.

Mean audiograms for a) PEX1 - G843D/Null, b) PEX1 – G843D/G843D, c) Other PEX Mutations – Intermediate & Mild, and d) DBPD groups. Right ear thresholds depicted as red circles and left ear thresholds in blue x’s. Lighter audiograms in each group represent mean audiograms from individual patients, while darker audiograms reflect mean group audiograms. Audiograms from 5 patients in the PEX1 - G843D/Null, 11 patients in the PEX1 – G843D/G843D, 15 patients in the Other PEX Mutations – Intermediate & Mild, and 3 patients in the DBPD groups were used to calculate mean audiograms. Errors bars represent standard deviation.

Figure 2:

Air-bone gaps as a function of age for the combined datasets of both ears at a) 0.5 kHz, b) 1.0 kHz, c) 2.0 kHz, and d) 4.0 kHz, shown for each patient group. The horizontal shaded area denotes ±10 dB air-bone gap limit and the vertical dotted line denotes pediatric age limit of 18 years.

Figure 3:

Shifts in 4F-PTA (four-frequency PTA based on 0.5 – 4 kHz) between consecutive test dates as a function of time between tests. Shifts were calculated by subtracting older test-date thresholds from more recent test-date thresholds (i.e. positive shift indicates decline in hearing). a) Right ear and b) left ear air conduction and c) bone conduction shifts combined from both ears in 4F-PTA are shown. Different groups are denoted by different shapes, with right ear threshold shifts depicted in red and left ear shifts in blue. The shaded area represents accepted test-retest variability of +/− 10dB.

Figure 4:

Longitudinal changes in hearing for 27 patients with multiple audiograms (a total of 186 audiograms) shown as the mean (+/− 1 standard deviation) air-conduction pure tone threshold at baseline and at the final audiogram for the a) right and c) left ears; c) individual patient’s ear specific progression of the 4F-PTA as a function of age for the right (red) and left (blue) ears; a linear mixed effects regression model based on 4F-PTA are shown by the solid black line.