Molecular Genetics and Metabolism 111 (2014) 533–538
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Assessment of hearing loss by pure-tone audiometry in patients with mucopolysaccharidoses Hsiang-Yu Lin a,b,c,d,e, Shou-Chuan Shih a,f, Chih-Kuang Chuang c,g,h, Kuo-Sheng Lee a,d,i,j, Ming-Ren Chen a,b,d, Hung-Ching Lin a,i,j, Pao Chin Chiu k, Dau-Ming Niu e,l, Shuan-Pei Lin a,b,c,d,m,⁎ a
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan d Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan e Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan f Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan g Medical College, Fu-Jen Catholic University, Taipei, Taiwan h Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan i Department of Otorhinolaryngology, Mackay Memorial Hospital, Taipei, Taiwan j Department of Audiology & Speech Language Pathology, Mackay Medical College, New Taipei City, Taiwan k Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan l Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan m Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 8 January 2014 Received in revised form 6 February 2014 Accepted 9 February 2014 Available online 16 February 2014 Keywords: Enzyme replacement therapy Hearing loss Mucopolysaccharidoses Pure-tone audiometry
a b s t r a c t Background: Patients with mucopolysaccharidoses (MPS) often have hearing loss. However, the characterization of hearing loss by pure-tone audiometry (PTA) in this rare disease population and its relationship to age and treatment is limited. Methods: PTA was performed in 39 patients with MPS (29 males and 10 females; 3 with MPS I, 21 with MPS II, 9 with MPS IVA, and 6 with MPS VI; median age, 11.9 years; age range, 4.4–34.2 years). The degree of hearing loss was classified by the age-independent World Health Organization (WHO) clinical guidelines. Results: Hearing loss by PTA was present in 85% (33/39) of patients and was categorized as mild (26–40 dB) in 18%, moderate (41–60 dB) in 36%, severe (61–80 dB) in 23%, and profound (≥81 dB) in 5%. Among the patients with hearing loss, 33% were classified as mixed type (conductive and sensorineural), 30% as pure conductive type, 27% as pure sensorineural type, and 9% were undefined. The means of the right and left ear hearing thresholds at 2000 and 4000 Hz by air conduction (AC) and at 500, 1000, 2000, and 4000 Hz by bone conduction (BC) were all positively correlated with age (p b 0.05). In the 6 patients with MPS II or VI who underwent follow-up PTA after ventilation tube insertion and enzyme replacement therapy for 1.9 to 8.5 years, all showed improvements in AC and BC of the better ear, as well as in the air-bone gap. Conclusions: Hearing impairment is common in MPS. Early otolaryngological evaluation and intervention are recommended. These findings and the follow-up data can be used to develop quality of care strategies for patients with MPS. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The mucopolysaccharidoses (MPS; OMIM 252700) are a group of inherited lysosomal storage disorders caused by deficiencies in
Abbreviations: AC, air conduction; BC, bone conduction; CHL, conductive hearing loss; dB, decibel; ERT, enzyme replacement therapy; GAG, glycosaminoglycan; MPS, mucopolysaccharidoses; PTA, pure-tone audiometry; SNHL, sensorineural hearing loss. ⁎ Corresponding author at: Department of Pediatrics, Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei 10449, Taiwan. Fax: +886 2 2543 3642. E-mail address: [email protected] (S.-P. Lin).
http://dx.doi.org/10.1016/j.ymgme.2014.02.003 1096-7192/© 2014 Elsevier Inc. All rights reserved.
enzymes catalyzing the degradation of glycosaminoglycans (GAGs). Progressive lysosomal accumulation of GAGs results in profound growth deficits, skeletal deformities, hearing loss, poor joint mobility, coarse facial features, and organomegaly. Eleven known enzyme deficiencies give rise to 7 distinct types of MPS (I, II, III, IV, VI, VII, and IX). All are inherited in an autosomal recessive manner except for MPS II, which is an X-linked recessive disorder that occurs almost exclusively in males. Each MPS type exhibits a wide spectrum of clinical severity. Cases ranging from severe to attenuated exist for MPS I (Hurler, Hurler– Scheie and Scheie syndromes) and MPS II (Hunter syndrome), and additional subtypes have been described for MPS III and MPS IV [1,2].
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The prevalence of MPS as a group is reported to be 1.9–4.5/100,000 live births with geographical differences in the frequencies of specific types. In Taiwan and other Asian countries, the most common type is MPS II, whereas in most Caucasian countries, it is MPS I or MPS III [3]. Patients with MPS often have hearing loss that can be attributed to multiple causes. Conductive hearing loss (CHL) is usually secondary to recurrent upper respiratory tract infection and serous otitis media, or a deformity of the bony ossicles. Sensorineural hearing loss (SNHL) may result from GAG accumulation in the cochlea, auditory nerve, and brainstem. Most patients show “mixed” hearing loss with combined conductive and sensorineural components. While ventilation tubes are often used to treat CHL resulting from middle ear effusion, hearing aids are required for SNHL [4–7]. Pure-tone audiometry (PTA) is a useful hearing test that can be used to determine hearing threshold levels in an individual and for characterizing the degree, type and configuration of hearing loss. PTA is a subjective and behavioral measurement of the hearing threshold that depends upon a patient's response to pure tone stimuli. PTA is performed in adults and in children who are old enough to follow instructions, and it provides the basis for the diagnosis and management of hearing loss [8]. In conjunction with PTA, tympanometry is used to evaluate the condition of the middle ear and the mobility of the eardrum and conduction bones by creating variations of air pressure in the ear canal. A normal tympanogram is labeled type A with normal pressure in the middle ear, and normal mobility of the eardrum and conduction bones. Types B and C tympanograms may indicate a middle ear effusion, perforation or scarring of the tympanic membrane, lack of contact between the conduction bones of the middle ear, or a tumor of the middle ear [9], distinguishing between SNHL and CHL. Hearing impairment is an important health problem for patients with MPS that may be prevented by early and diligent interventions. There are only a few published reports on the prevalence, common age of onset, and severity of hearing loss in MPS disorders [10,11]. Here, we describe the prevalence, type, and severity of hearing loss by PTA and tympanometry in a group of 39 MPS patients before surgical interventions or enzyme replacement therapy (ERT). We also evaluated the relationship between hearing loss and age, as well as the effect of treatment in 6 patients followed longitudinally.
3 patients with MPS I (Hurler/Scheie), 21 with attenuated MPS II, 9 with MPS IVA, and 6 with MPS VI [12]. Written informed consent was obtained from a parent for children less than 18 years and from patients who were 18 years or older. The study was approved by the ethics committee at Mackay Memorial Hospital, Taipei, Taiwan. 2.2. Assessments 2.2.1. Otolaryngologic and audiologic examinations Each patient's gender, age, and MPS type were recorded at baseline. A senior ear, nose, and throat specialist performed the otolaryngological evaluations. For each patient, information was collected on the otolaryngological manifestations and interventions, including otitis media, otorrhea, tinnitus, vertigo, tympanic membrane perforation, adenoidectomy, ventilation tube insertion, and hearing aids previously recorded in the patient's medical chart. PTA with air conduction (AC) threshold test frequencies of 250, 500, 1000, 2000, 4000, and 8000 Hz was performed in a quiet room by experienced audiologists using age-appropriate methods, with bone conduction (BC) thresholds and masking as appropriate. Audiologists recorded pure-tone hearing thresholds in decibel (dB) hearing level, detailing the AC and BC in a soundproof booth. 2.2.2. Types of hearing loss The types of hearing loss were classified as pure CHL, pure SNHL, and mixed according to the criteria of the Genetic Deafness study group [13]. A normal air-bone gap was defined as an average AC threshold (at 500, 1000, and 2000 Hz) ≤15 dB above the BC threshold. We defined pure CHL as an average BC threshold ≤20 dB with an average air-bone gap ≥15 dB, pure SNHL as an average BC threshold N 20 dB with an average air-bone gap b 15 dB, and mixed hearing loss as an average BC threshold N20 dB with an average air-bone gap of ≥15 dB. 2.2.3. Severity of hearing loss The World Health Organization (WHO) International Classification of Impairments, Disabilities and Handicaps (WHO-ICIDH) standard was used to categorize the degree of hearing loss seen in the PTAs used in this study [8,14]. WHO-ICIDH is independent of age and classifies hearing loss according to the threshold in the better ear. It is designed to determine the presence of clinically relevant hearing loss and communication difficulties. Using the WHO classification, the averages for PTA thresholds at 500, 1000, and 2000 Hz were classified as normal (0–25 dB) or hearing loss that was mild (26–40 dB), moderate (41–60 dB), severe (61–80 dB), or profound (≥81 dB).
2. Materials and methods 2.1. Study population Thirty-nine patients with MPS (29 males and 10 females; mean age, 14.0 ± 8.6 years; age range, 4.4–34.2 years) followed at Mackay Memorial Hospital were enrolled and evaluated in this study. All patients underwent a medical history for otolaryngological problems followed by PTA. None had received ERT, hematopoietic stem cell transplantation, ventilation tube insertion, or adenotonsillectomy prior to their baseline PTA. The diagnosis of MPS was confirmed by twodimensional electrophoresis of urinary GAGs and enzyme activity assays in serum, leukocytes and/or skin fibroblasts. Our cohort included
2.3. Statistical analysis Descriptive statistics were performed, and the results are presented as mean ± standard deviation (SD) unless otherwise indicated. Since the age range in this study was quite broad (4.4–34.2 years), the 39 patients were subdivided into 5 age groups to characterize hearing loss by age. The relationship between age and the means of the right and left
Table 1 Pure-tone audiometry (PTA) classification by MPS type in 39 patients. Values are displayed as mean (standard deviation). MPS type
MPS I MPS II MPS IVA MPS VI Total
n
3 21 9 6 39
Age, years
21.8 (12.6) 14.3 (9.2) 13.8 (6.9) 9.1 (3.9) 14 (8.6)
Age range, years
7.9–32.3 4.7–34.2 5.3–26.8 4.4–14.4 4.4–34.2
PTA classification Normal
1 2 3 0 6
Abnormal Mixed HL
Pure CHL
Pure SNHL
HL type undefined
0 7 3 1 11
1 3 1 5 10
1 7 1 0 9
0 2a 1a 0 3a
AC in better ear (dB) (n = 39)
BC in better ear (dB) (n = 34)
Air-bone gap (dB) (n = 34)
33.9 (21.1) 51 (20.7) 47.8 (28) 40.6 (10.9) 47.3 (21.4)
12.8 (7.7) 36.3 (19.9) 29.3 (17.9) 13 (7.5) 28.7 (19.3)
21.1 (23.6) 18.4 (14.7) 20.3 (14.9) 27.5 (6.7) 20.6 (14.3)
MPS, mucopolysaccharidoses; HL, hearing loss; CHL, conductive hearing loss; SNHL, sensorineural hearing loss; AC, air conduction; BC, bone conduction. a The values of bone conduction were not available for these patients.
Percentage of Patients per Age Groups
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70%
Normal
60%
Pure CHL
50%
Mixed HL
3. Results
40%
Pure SNHL
30%
HL type undefined
The 39 MPS patients (29 males and 10 females) were evenly distributed by age from 4.4 years to early adulthood. The abundance of males was attributable to the 21 male patients with MPS II, an X-linked recessive disorder. By medical history, there was a high prevalence of otolaryngological manifestations and interventions, with 27 (69%) patients reported having had otitis media, 21 (54%) otorrhea, 6 (15%) tympanic membrane perforation, 3 (8%) tinnitus, and 2 (5%) vertigo. Nineteen (49%) patients reported having undergone insertion of ventilation tubes and 8 (21%) adenoidectomy. Eight (21%) patients required hearing aids. Table 1 shows the PTA classification according to MPS type. AC results were available for all 39 patients. However, due to the unavailability of BC results in 5 patients, only 34 patients had air-bone gap results. Mean AC and BC for the better ear were both increased at 47.3 dB (moderate hearing loss) and 28.7 dB (mild hearing loss), respectively. The mean air-bone gap also was increased at 20.6 dB (normal b 15 dB). An abnormal air-bone gap (≥ 15 dB) was found in 21 patients (62%), demonstrating involvement of a CHL component
performed using Fisher's r-z transformations. All statistical analyses were performed using SPSS version 11.5 (SPSS Inc., Chicago, IL, USA).
20% 10% 0%
0-5 (n=8)
6-10 (n=10)
11-15 (n=8)
16-20 (n=5)
>21 (n=8)
Age (yr) Fig. 1. Prevalence of different types of hearing loss by age group for 39 patients with mucopolysaccharidoses. CHL, conductive hearing loss; HL, hearing loss; SNHL, sensorineural hearing loss.
ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for both AC and BC in these MPS patients was evaluated using Pearson's correlation coefficient (r), and testing for statistical significance (p b 0.05) was
a
b
Air conduction 500 Hz (n=39) r=0.220 p> 0.05
Mean Threshold (dB)
Mean Threshold (dB)
r=0.303 p> 0.05
100
80
60
40
20
0
Air conduction 1000 Hz (n=39) 120
100
80 60 40 20
0
10
20
30
0 0
40
10
Age (Years)
c
30
40
d Air conduction 2000 Hz (n=39) 120
Air conduction 4000 Hz (n=39) 120
r=0.407 p< 0.05
100
80
60
40
20
0 0
r=0.319 p< 0.05
100
Mean Threshold (dB)
Mean Threshold (dB)
20
Age (Years)
80
60
40
20
10
20
Age (Years)
30
40
0
0
10
20
30
40
Age (Years)
Fig. 2. Ages and means of the right and left ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for air conduction in patients with mucopolysaccharidoses (n = 39). The mean hearing thresholds for air conduction at 2000 (2c) and 4000 Hz (2d) increased with age (p b 0.05).
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(including mixed hearing loss and pure CHL). Hearing loss was identified by PTA in 33 patients: 11 (33%) with mixed type, 10 (30%) with pure CHL, 9 (27%) with pure SNHL, and 3 (9%) with undefined hearing loss. Patient's age was positively correlated with the presence of the SNHL component (r = 0.505, p b 0.01). Regarding the severity of hearing loss, according to the WHO classification, only 6 patients (15%) had normal hearing (≤25 dB) while 33 had hearing loss, which was mild (26–40 dB) in 8 (21%), moderate (41–60 dB) in 14 (36%), severe (61–80 dB) in 9 (23%), and profound (≥81 dB) in 2 (5%). Fig. 1 shows the percentages of patients with different types of hearing loss within each age group. The mean right and left ear hearing thresholds at 2000 and 4000 Hz for AC, and at 500, 1000, 2000, and 4000 Hz for BC, were all positively correlated with age (p b 0.05) (Figs. 2 and 3). Tympanograms were performed on 57 ears, and 30% were classified as type A (normal), 51% as type B, and 19% as type C. All 6 patients with MPS II and VI who had follow-up PTA after undergoing ventilation tube insertion and receiving ERT for 1.9 to 8.5 years showed improvements in AC and BC of the better ear, as well as a decrease in the air-bone gap (Table 2). 4. Discussion To the best of our knowledge, this is the largest single center study of MPS patients evaluated for hearing loss using PTA prior to ventilation tube insertion and the initiation of ERT. We found that 85% (33/39) of
a
the MPS patients had varying degrees of hearing loss that was mostly in the mild to severe range. This high prevalence of hearing loss is consistent with data from the Hunter Outcome Survey (HOS) of MPS II patients reported by Keilmann et al. [11] [84% (n = 83)] and from another study of MPS I, II, and VI patients performed by Napiontek and Keilmann [10] [89% (n = 35)]. Among our 33 patients with hearing loss and complete PTA data, the most common classification was mixed type hearing loss in 33% (11/33). Similarly, Napiontek and Keilmann [10], Wold et al. [6], and Keilmann et al. [11] found that 51%, 71%, and 33% of their study subjects had mixed hearing loss, respectively. By cross-sectional analysis, older patients in our cohort had higher AC and BC hearing thresholds than younger patients, suggesting a worsening of hearing loss over time as expected given the progressive nature of MPS. Our finding also agrees with that of Keilmann et al. [11]. In our study, pure CHL was the most common type of hearing loss observed in younger MPS patients. With increasing age, SNHL became apparent, such that the majority of MPS patients in the older age groups exhibited mixed hearing loss or pure SNHL (Fig. 1). Interestingly, only MPS II had a significant number of patients with pure SNHL (n = 7). In other types of MPS, most cases of hearing loss were mixed or pure CHL. Our results are similar to those cited in previous reports [10,11]. However, the exact reason for the different types of hearing loss observed according to MPS type is unclear, but likely relates to the specific nature and secondary effects of the accumulated GAG substrates.
b
Bone conduction 1000 Hz (n=34)
Bone conduction 500 Hz (n=34) 80 80
r=0.539 p< 0.05
60
Mean Threshold (dB)
Mean Threshold (dB)
r=0.503 p< 0.05
40
20
0
0
10
20
30
60
40
20
0 0
40
10
Age (Years)
c
30
40
d Bone conduction 2000 Hz (n=34)
Bone conduction 4000 Hz (n=34) 80
80
60
40
20
0 0
r=0.510 p< 0.05
r=0.539 p< 0.05 Mean Threshold (dB)
Mean Threshold (dB)
20
Age (Years)
60
40
20
0 10
20
Age (Years)
30
40
0
10
20
30
40
Age (Years)
Fig. 3. Ages and means of the right and left ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for bone conduction in patients with mucopolysaccharidoses (n = 34). The mean hearing thresholds for bone conduction at all four frequencies (3a–3d) increased with age (p b 0.05).
1
3
2
1
2
4
46.7 20 8.3 5 43.4 5 35 13.3 36.6 20 23.4 16.7 3.3 1.7 55 45 23.3 23.3 0 0 11.7 5 3.3 0 10 5 61.7 55 48.3 30 0 0 11.7 8.3 3.3 0 3.3 1.7 55 45 23.3 23.3 0 6.7 25 5 3.3 0 50 21.7 63.3 50 66.7 28.3 35 13.3 48.3 25 26.7 16.7 M MPS VI 6
M MPS VI 5
F MPS VI 4
MPS, mucopolysaccharidoses; AC, air conduction; BC, bone conduction.
6.3
5.2
8.5
1.9 MPS II 3
M
MPS II 2
M
4.7 10.7 17.6 23.5 15.0 16.9 11.7 20.2 7.5 12.7 8.3 14.6 MPS II 1
M
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
5.9
50 21.7 63.3 50 66.7 28.3 35 25 51.7 25 28.3 23.3 6.0
50 25 78.3 60 75.0 71.7 40 13.3 48.3 46.7 26.7 16.7
Times of ventilation tube insertion Air-bone gap (dB) BC (better ear) (dB) BC (left ear) BC (right ear) AC (better ear) (dB) AC (left ear) AC (right ear) ERT duration (yr) Age at PTA (yr) PTA Gender MPS type No.
Table 2 Baseline and follow-up pure-tone audiometry (PTA) parameters of 6 patients with MPS II or MPS VI who underwent ventilation tube insertion and received enzyme replacement therapy (ERT) for 1.9 to 8.5 years.
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Although the insertion of ventilation tubes can improve CHL resulting from chronic otitis media with effusion, ventilation tubes will obviously not ameliorate SNHL, either alone or as a component of mixed hearing loss. In our results, all 6 patients with MPS II or VI improved their air-bone gap values (CHL component) after ventilation tube insertion and ERT, which has become available for the treatment of patients with some lysosomal storage diseases. Previous publications demonstrated that ERT delays the onset of hearing loss and reduces the severity of SNHL in Fabry disease [15,16]. However, for MPS, there is a paucity of literature describing the effects of ERT on hearing loss. A recent report by Brands et al. [17] describes that 2 out of 3 patients with MPS VI improved CHL after ERT, due possibly to ERT-related decrease in upper airway infections. Another study in MPS II mice suggests that although early initiation of ERT might prevent CHL, SNHL might not be prevented in the long term [18]. O'Connor et al. [19] reported that some learning, memory, and hearing deficits can be prevented in MPS VII mice if ERT is initiated early in life. In our study, all 6 patients with MPS II or VI improved or stabilized their BC values (SNHL component) after receiving ERT for 1.9 to 8.5 years (Table 2). Improvement of CHL in MPS patients receiving ERT is probably due to decrease in upper airway infections, as well as reducing middle ear effusions causing pressure on the Eustachian tube. However, it remains unclear whether SNHL has a congenital basis or is acquired secondarily to deposition of GAGs in the inner ear or central nervous system [20]. The issue concerning the effect of ERT for MPS on SNHL can be resolved only after longer follow-up. Our findings support PTA as a clinically useful method for monitoring hearing loss in MPS patients and assessing its response to ventilation tubes insertion or ERT. PTA is a well-recognized and quantitative measure for assessment of hearing loss, and all of our test results were analyzed by a single expert in PTA to avoid inter-examiner variability. There is very little published literature on the characteristics of tympanograms in MPS patients. In our study, only 30% of the tympanograms were classified as type A (normal), and 70% as types B or C. Further research is needed to determine which of the multiple mechanisms responsible for the abnormal air-bone gap and BC are most impacted by ERT. Our study has several limitations. Study patients had to be cooperative and capable of following instructions for the PTA to be performed. Consequently, patients with severe forms of MPS I–III were naturally excluded by the study design. Although auditory brainstem response is an objective test of hearing threshold that does not require the patient's cooperation, the risks of sedation for MPS patients make it difficult to use in routine clinical practice [11]. The age range of patients in our study was quite broad (4.4–34.2 years), and the number of patients was too small to draw definite conclusions about differences between MPS types. Despite these limitations, our results are consistent with those of other case series in the literature that report a high prevalence of hearing loss among MPS patients, warranting further exploration of the issue in a larger cohort.
5. Conclusion We found a high prevalence of hearing loss (85%) of varying types and severity by PTA in a cohort of 39 MPS patients unselected for auditory problems. All 6 patients with MPS II or VI showed improvements in AC, BC, and air-bone gap by PTA after receiving ventilation tube insertion and ERT for 1.9–8.5 years. PTA is a simple, accurate, and noninvasive method for measuring the type and severity of hearing loss, and we recommend screening and regular monitoring of hearing loss by PTA for patients with MPS. Findings of hearing impairment may alert clinicians and caregivers of MPS patients to take prompt appropriate counseling and intervention for their better future developments in communication, language, emotion, and behavioral regulation.
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Acknowledgments We acknowledge the participation of study patients and their families. This study was supported by the research grants from the National Science Council, Taiwan (NSC-102-2314-B-195-006 and NSC-1022314-B-195-017-MY3), and Mackay Memorial Hospital (MMH-101111 and MMH-I-S-600). We would like to express our sincere thanks to Gerald F. Cox, M.D., Ph.D. (Genzyme, a Sanofi Company) for his critical review and valuable comments, and Ms. Tsai-Feng Ho for her professional assistance in biostatistics. Conflict of interest statement The authors declare that they have no competing interests. Authors' contributions HYL performed acquisition, statistical analysis and interpretation of data, and drafting of the manuscript. SPL participated in design of the study, interpretation of the data and helped to draft the manuscript. CKC performed biochemical analyses and revised the manuscript. SCS, KSL, MRC, HCL, PCC and DMN were responsible for patient screening. All authors read and accepted the manuscript. References [1] E.F. Neufeld, J. Muenzer, The mucopolysaccharidoses, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle, B. Childs, K.W. Kinzler, B. Vogelstein (Eds.), The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York, 2001, pp. 3421–3452. [2] C.K. Chuang, S.P. Lin, Neurochemical changes and therapeutical approaches in mucopolysaccharidoses, in: Sankar Surendran, Michael Aschner, Maheep Bhatnagar (Eds.), Neurochemistry of Metabolic Diseases—Lysosomal Storage Diseases, Phenylketonuria and Canavan Disease, Transworld Research Network, Trivandrum, India, 2007, pp. 1–20. [3] H.Y. Lin, S.P. Lin, C.K. Chuang, D.M. Niu, M.R. Chen, F.J. Tsai, M.C. Chao, P.C. Chiu, S.J. Lin, L.P. Tsai, W.L. Hwu, J.L. Lin, Incidence of the mucopolysaccharidoses in Taiwan, 1984–2004, Am. J. Med. Genet. A. 149A (2009) 960–964. [4] E. Schleier, H.G. Streubel, Phoniatric aspects of children with mucopolysaccharidosis, Folia. Phoniatr. (Basel). 28 (1976) 65–72.
[5] J.E. Peck, Hearing loss in Hunter's syndrome—mucopolysaccharidosis II, Ear. Hear. 5 (1984) 243–246. [6] S.M. Wold, C.S. Derkay, D.H. Darrow, V. Proud, Role of the pediatric otolaryngologist in diagnosis and management of children with mucopolysaccharidoses, Int. J. Pediatr. Otorhinolaryngol. 74 (2010) 27–31. [7] C.J. Hendriksz, M. Al-Jawad, K.I. Berger, S.M. Hawley, R. Lawrence, C. Mc Ardle, C.G. Summers, E. Wright, E. Braunlin, Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA, J. Inherit. Metab. Dis. 36 (2013) 309–322. [8] World Health Organization, WHO ear and hearing disorders survey protocol for a population-based survey of prevalence and causes of deafness and hearing impairment and other ear disorders, Retrieved from http://whqlibdoc.who.int/hq/1999/ WHO_PBD_PDH_99.8(1).pdf1999 (on 05-11-13). [9] D.J. Steele, J. Susman, F.A. McCurdy, Student guide to primary care: making the most of your early clinical experience, Elsevier Health Sciences, 2003, pp. 370–392, (ISBN 978-1-56053-545-4). [10] U. Napiontek, A. Keilmann, Hearing impairment in patients with mucopolysaccharidoses, Acta. Paediatrica. Suppl. 451 (2006) 114. [11] A. Keilmann, T. Nakarat, I.A. Bruce, D. Molter, G. Malm, HOS Investigators, Hearing loss in patients with mucopolysaccharidosis II: data from HOS — the Hunter Outcome Survey, J. Inherit. Metab. Dis. 35 (2012) 343–353. [12] C.K. Chuang, S.P. Lin, S.F. Chung, Diagnostic screening for mucopolysaccharidoses by the dimethylmethylene blue method and two dimensional electrophoresis, Zhonghua. Yi. Xue. Za. Zhi. (Taipei). 64 (2001) 15–22. [13] M. Mazzoli, G.V. Camp, V. Newton, N. Girbini, F. Declau, A. Parving, Recommendation for the description of genetic and audiological data for families with nonsyndromic heredity hearing impairment, Audiolog. Med. 1 (2003) 148–150. [14] D. Pascolini, A. Smith, Hearing impairment in 2008: a compilation of available epidemiological studies, Int. J. Audiol. 48 (2009) 473–485. [15] D. Hajioff, S. Hegemann, G. Conti, M. Beck, G. Sunder-Plassmann, U. Widmer, A. Mehta, A. Keilmann, Agalsidase alpha and hearing in Fabry disease: data from the Fabry Outcome Survey, Eur. J. Clin. Invest. 36 (2006) 663–667. [16] M. Komori, Y. Sakurai, H. Kojima, T. Ohashi, H. Moriyama, Long-term effect of enzyme replacement therapy with Fabry disease, Int. J. Otolaryngol. 2013 (2013) 282487. [17] M.M. Brands, E. Oussoren, G.J. Ruijter, A.A. Vollebregt, H.M. van den Hout, K.F. Joosten, W.C. Hop, I. Plug, A.T. van der Ploeg, Up to five years experience with 11 mucopolysaccharidosis type VI patients, Mol. Genet. Metab. 109 (2013) 70–76. [18] S.H. Hong, H. Chu, K.R. Kim, M.H. Ko, S.Y. Kwon, I.J. Moon, W.H. Chung, Y.S. Cho, C.H. Kim, M.W. Suh, E.W. Choi, Y.B. Sohn, S.W. Park, S.H. Kim, S.Y. Cho, A.R. Ko, D.K. Jin, Auditory characteristics and therapeutic effects of enzyme replacement in mouse model of the mucopolysaccharidosis (MPS) II, Am. J. Med. Genet. A. 158A (2012) 2131–2138. [19] L.H. O'Connor, L.C. Erway, C.A. Vogler, W.S. Sly, A. Nicholes, J. Grubb, S.W. Holmberg, B. Levy, M.S. Sands, Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function, J. Clin. Invest. 101 (1998) 1394–1400. [20] M.A. Simmons, I.A. Bruce, S. Penney, E. Wraith, M.P. Rothera, Otorhinolaryngological manifestations of the mucopolysaccharidoses, Int. J. Pediatr. Otorhinolaryngol. 69 (2005) 589–595.
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Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Assessment of hearing loss by pure-tone audiometry in patients with mucopolysaccharidoses Hsiang-Yu Lin a,b,c,d,e, Shou-Chuan Shih a,f, Chih-Kuang Chuang c,g,h, Kuo-Sheng Lee a,d,i,j, Ming-Ren Chen a,b,d, Hung-Ching Lin a,i,j, Pao Chin Chiu k, Dau-Ming Niu e,l, Shuan-Pei Lin a,b,c,d,m,⁎ a
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan d Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan e Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan f Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan g Medical College, Fu-Jen Catholic University, Taipei, Taiwan h Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan i Department of Otorhinolaryngology, Mackay Memorial Hospital, Taipei, Taiwan j Department of Audiology & Speech Language Pathology, Mackay Medical College, New Taipei City, Taiwan k Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan l Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan m Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 8 January 2014 Received in revised form 6 February 2014 Accepted 9 February 2014 Available online 16 February 2014 Keywords: Enzyme replacement therapy Hearing loss Mucopolysaccharidoses Pure-tone audiometry
a b s t r a c t Background: Patients with mucopolysaccharidoses (MPS) often have hearing loss. However, the characterization of hearing loss by pure-tone audiometry (PTA) in this rare disease population and its relationship to age and treatment is limited. Methods: PTA was performed in 39 patients with MPS (29 males and 10 females; 3 with MPS I, 21 with MPS II, 9 with MPS IVA, and 6 with MPS VI; median age, 11.9 years; age range, 4.4–34.2 years). The degree of hearing loss was classified by the age-independent World Health Organization (WHO) clinical guidelines. Results: Hearing loss by PTA was present in 85% (33/39) of patients and was categorized as mild (26–40 dB) in 18%, moderate (41–60 dB) in 36%, severe (61–80 dB) in 23%, and profound (≥81 dB) in 5%. Among the patients with hearing loss, 33% were classified as mixed type (conductive and sensorineural), 30% as pure conductive type, 27% as pure sensorineural type, and 9% were undefined. The means of the right and left ear hearing thresholds at 2000 and 4000 Hz by air conduction (AC) and at 500, 1000, 2000, and 4000 Hz by bone conduction (BC) were all positively correlated with age (p b 0.05). In the 6 patients with MPS II or VI who underwent follow-up PTA after ventilation tube insertion and enzyme replacement therapy for 1.9 to 8.5 years, all showed improvements in AC and BC of the better ear, as well as in the air-bone gap. Conclusions: Hearing impairment is common in MPS. Early otolaryngological evaluation and intervention are recommended. These findings and the follow-up data can be used to develop quality of care strategies for patients with MPS. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The mucopolysaccharidoses (MPS; OMIM 252700) are a group of inherited lysosomal storage disorders caused by deficiencies in
Abbreviations: AC, air conduction; BC, bone conduction; CHL, conductive hearing loss; dB, decibel; ERT, enzyme replacement therapy; GAG, glycosaminoglycan; MPS, mucopolysaccharidoses; PTA, pure-tone audiometry; SNHL, sensorineural hearing loss. ⁎ Corresponding author at: Department of Pediatrics, Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei 10449, Taiwan. Fax: +886 2 2543 3642. E-mail address: [email protected] (S.-P. Lin).
http://dx.doi.org/10.1016/j.ymgme.2014.02.003 1096-7192/© 2014 Elsevier Inc. All rights reserved.
enzymes catalyzing the degradation of glycosaminoglycans (GAGs). Progressive lysosomal accumulation of GAGs results in profound growth deficits, skeletal deformities, hearing loss, poor joint mobility, coarse facial features, and organomegaly. Eleven known enzyme deficiencies give rise to 7 distinct types of MPS (I, II, III, IV, VI, VII, and IX). All are inherited in an autosomal recessive manner except for MPS II, which is an X-linked recessive disorder that occurs almost exclusively in males. Each MPS type exhibits a wide spectrum of clinical severity. Cases ranging from severe to attenuated exist for MPS I (Hurler, Hurler– Scheie and Scheie syndromes) and MPS II (Hunter syndrome), and additional subtypes have been described for MPS III and MPS IV [1,2].
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The prevalence of MPS as a group is reported to be 1.9–4.5/100,000 live births with geographical differences in the frequencies of specific types. In Taiwan and other Asian countries, the most common type is MPS II, whereas in most Caucasian countries, it is MPS I or MPS III [3]. Patients with MPS often have hearing loss that can be attributed to multiple causes. Conductive hearing loss (CHL) is usually secondary to recurrent upper respiratory tract infection and serous otitis media, or a deformity of the bony ossicles. Sensorineural hearing loss (SNHL) may result from GAG accumulation in the cochlea, auditory nerve, and brainstem. Most patients show “mixed” hearing loss with combined conductive and sensorineural components. While ventilation tubes are often used to treat CHL resulting from middle ear effusion, hearing aids are required for SNHL [4–7]. Pure-tone audiometry (PTA) is a useful hearing test that can be used to determine hearing threshold levels in an individual and for characterizing the degree, type and configuration of hearing loss. PTA is a subjective and behavioral measurement of the hearing threshold that depends upon a patient's response to pure tone stimuli. PTA is performed in adults and in children who are old enough to follow instructions, and it provides the basis for the diagnosis and management of hearing loss [8]. In conjunction with PTA, tympanometry is used to evaluate the condition of the middle ear and the mobility of the eardrum and conduction bones by creating variations of air pressure in the ear canal. A normal tympanogram is labeled type A with normal pressure in the middle ear, and normal mobility of the eardrum and conduction bones. Types B and C tympanograms may indicate a middle ear effusion, perforation or scarring of the tympanic membrane, lack of contact between the conduction bones of the middle ear, or a tumor of the middle ear [9], distinguishing between SNHL and CHL. Hearing impairment is an important health problem for patients with MPS that may be prevented by early and diligent interventions. There are only a few published reports on the prevalence, common age of onset, and severity of hearing loss in MPS disorders [10,11]. Here, we describe the prevalence, type, and severity of hearing loss by PTA and tympanometry in a group of 39 MPS patients before surgical interventions or enzyme replacement therapy (ERT). We also evaluated the relationship between hearing loss and age, as well as the effect of treatment in 6 patients followed longitudinally.
3 patients with MPS I (Hurler/Scheie), 21 with attenuated MPS II, 9 with MPS IVA, and 6 with MPS VI [12]. Written informed consent was obtained from a parent for children less than 18 years and from patients who were 18 years or older. The study was approved by the ethics committee at Mackay Memorial Hospital, Taipei, Taiwan. 2.2. Assessments 2.2.1. Otolaryngologic and audiologic examinations Each patient's gender, age, and MPS type were recorded at baseline. A senior ear, nose, and throat specialist performed the otolaryngological evaluations. For each patient, information was collected on the otolaryngological manifestations and interventions, including otitis media, otorrhea, tinnitus, vertigo, tympanic membrane perforation, adenoidectomy, ventilation tube insertion, and hearing aids previously recorded in the patient's medical chart. PTA with air conduction (AC) threshold test frequencies of 250, 500, 1000, 2000, 4000, and 8000 Hz was performed in a quiet room by experienced audiologists using age-appropriate methods, with bone conduction (BC) thresholds and masking as appropriate. Audiologists recorded pure-tone hearing thresholds in decibel (dB) hearing level, detailing the AC and BC in a soundproof booth. 2.2.2. Types of hearing loss The types of hearing loss were classified as pure CHL, pure SNHL, and mixed according to the criteria of the Genetic Deafness study group [13]. A normal air-bone gap was defined as an average AC threshold (at 500, 1000, and 2000 Hz) ≤15 dB above the BC threshold. We defined pure CHL as an average BC threshold ≤20 dB with an average air-bone gap ≥15 dB, pure SNHL as an average BC threshold N 20 dB with an average air-bone gap b 15 dB, and mixed hearing loss as an average BC threshold N20 dB with an average air-bone gap of ≥15 dB. 2.2.3. Severity of hearing loss The World Health Organization (WHO) International Classification of Impairments, Disabilities and Handicaps (WHO-ICIDH) standard was used to categorize the degree of hearing loss seen in the PTAs used in this study [8,14]. WHO-ICIDH is independent of age and classifies hearing loss according to the threshold in the better ear. It is designed to determine the presence of clinically relevant hearing loss and communication difficulties. Using the WHO classification, the averages for PTA thresholds at 500, 1000, and 2000 Hz were classified as normal (0–25 dB) or hearing loss that was mild (26–40 dB), moderate (41–60 dB), severe (61–80 dB), or profound (≥81 dB).
2. Materials and methods 2.1. Study population Thirty-nine patients with MPS (29 males and 10 females; mean age, 14.0 ± 8.6 years; age range, 4.4–34.2 years) followed at Mackay Memorial Hospital were enrolled and evaluated in this study. All patients underwent a medical history for otolaryngological problems followed by PTA. None had received ERT, hematopoietic stem cell transplantation, ventilation tube insertion, or adenotonsillectomy prior to their baseline PTA. The diagnosis of MPS was confirmed by twodimensional electrophoresis of urinary GAGs and enzyme activity assays in serum, leukocytes and/or skin fibroblasts. Our cohort included
2.3. Statistical analysis Descriptive statistics were performed, and the results are presented as mean ± standard deviation (SD) unless otherwise indicated. Since the age range in this study was quite broad (4.4–34.2 years), the 39 patients were subdivided into 5 age groups to characterize hearing loss by age. The relationship between age and the means of the right and left
Table 1 Pure-tone audiometry (PTA) classification by MPS type in 39 patients. Values are displayed as mean (standard deviation). MPS type
MPS I MPS II MPS IVA MPS VI Total
n
3 21 9 6 39
Age, years
21.8 (12.6) 14.3 (9.2) 13.8 (6.9) 9.1 (3.9) 14 (8.6)
Age range, years
7.9–32.3 4.7–34.2 5.3–26.8 4.4–14.4 4.4–34.2
PTA classification Normal
1 2 3 0 6
Abnormal Mixed HL
Pure CHL
Pure SNHL
HL type undefined
0 7 3 1 11
1 3 1 5 10
1 7 1 0 9
0 2a 1a 0 3a
AC in better ear (dB) (n = 39)
BC in better ear (dB) (n = 34)
Air-bone gap (dB) (n = 34)
33.9 (21.1) 51 (20.7) 47.8 (28) 40.6 (10.9) 47.3 (21.4)
12.8 (7.7) 36.3 (19.9) 29.3 (17.9) 13 (7.5) 28.7 (19.3)
21.1 (23.6) 18.4 (14.7) 20.3 (14.9) 27.5 (6.7) 20.6 (14.3)
MPS, mucopolysaccharidoses; HL, hearing loss; CHL, conductive hearing loss; SNHL, sensorineural hearing loss; AC, air conduction; BC, bone conduction. a The values of bone conduction were not available for these patients.
Percentage of Patients per Age Groups
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535
70%
Normal
60%
Pure CHL
50%
Mixed HL
3. Results
40%
Pure SNHL
30%
HL type undefined
The 39 MPS patients (29 males and 10 females) were evenly distributed by age from 4.4 years to early adulthood. The abundance of males was attributable to the 21 male patients with MPS II, an X-linked recessive disorder. By medical history, there was a high prevalence of otolaryngological manifestations and interventions, with 27 (69%) patients reported having had otitis media, 21 (54%) otorrhea, 6 (15%) tympanic membrane perforation, 3 (8%) tinnitus, and 2 (5%) vertigo. Nineteen (49%) patients reported having undergone insertion of ventilation tubes and 8 (21%) adenoidectomy. Eight (21%) patients required hearing aids. Table 1 shows the PTA classification according to MPS type. AC results were available for all 39 patients. However, due to the unavailability of BC results in 5 patients, only 34 patients had air-bone gap results. Mean AC and BC for the better ear were both increased at 47.3 dB (moderate hearing loss) and 28.7 dB (mild hearing loss), respectively. The mean air-bone gap also was increased at 20.6 dB (normal b 15 dB). An abnormal air-bone gap (≥ 15 dB) was found in 21 patients (62%), demonstrating involvement of a CHL component
performed using Fisher's r-z transformations. All statistical analyses were performed using SPSS version 11.5 (SPSS Inc., Chicago, IL, USA).
20% 10% 0%
0-5 (n=8)
6-10 (n=10)
11-15 (n=8)
16-20 (n=5)
>21 (n=8)
Age (yr) Fig. 1. Prevalence of different types of hearing loss by age group for 39 patients with mucopolysaccharidoses. CHL, conductive hearing loss; HL, hearing loss; SNHL, sensorineural hearing loss.
ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for both AC and BC in these MPS patients was evaluated using Pearson's correlation coefficient (r), and testing for statistical significance (p b 0.05) was
a
b
Air conduction 500 Hz (n=39) r=0.220 p> 0.05
Mean Threshold (dB)
Mean Threshold (dB)
r=0.303 p> 0.05
100
80
60
40
20
0
Air conduction 1000 Hz (n=39) 120
100
80 60 40 20
0
10
20
30
0 0
40
10
Age (Years)
c
30
40
d Air conduction 2000 Hz (n=39) 120
Air conduction 4000 Hz (n=39) 120
r=0.407 p< 0.05
100
80
60
40
20
0 0
r=0.319 p< 0.05
100
Mean Threshold (dB)
Mean Threshold (dB)
20
Age (Years)
80
60
40
20
10
20
Age (Years)
30
40
0
0
10
20
30
40
Age (Years)
Fig. 2. Ages and means of the right and left ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for air conduction in patients with mucopolysaccharidoses (n = 39). The mean hearing thresholds for air conduction at 2000 (2c) and 4000 Hz (2d) increased with age (p b 0.05).
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(including mixed hearing loss and pure CHL). Hearing loss was identified by PTA in 33 patients: 11 (33%) with mixed type, 10 (30%) with pure CHL, 9 (27%) with pure SNHL, and 3 (9%) with undefined hearing loss. Patient's age was positively correlated with the presence of the SNHL component (r = 0.505, p b 0.01). Regarding the severity of hearing loss, according to the WHO classification, only 6 patients (15%) had normal hearing (≤25 dB) while 33 had hearing loss, which was mild (26–40 dB) in 8 (21%), moderate (41–60 dB) in 14 (36%), severe (61–80 dB) in 9 (23%), and profound (≥81 dB) in 2 (5%). Fig. 1 shows the percentages of patients with different types of hearing loss within each age group. The mean right and left ear hearing thresholds at 2000 and 4000 Hz for AC, and at 500, 1000, 2000, and 4000 Hz for BC, were all positively correlated with age (p b 0.05) (Figs. 2 and 3). Tympanograms were performed on 57 ears, and 30% were classified as type A (normal), 51% as type B, and 19% as type C. All 6 patients with MPS II and VI who had follow-up PTA after undergoing ventilation tube insertion and receiving ERT for 1.9 to 8.5 years showed improvements in AC and BC of the better ear, as well as a decrease in the air-bone gap (Table 2). 4. Discussion To the best of our knowledge, this is the largest single center study of MPS patients evaluated for hearing loss using PTA prior to ventilation tube insertion and the initiation of ERT. We found that 85% (33/39) of
a
the MPS patients had varying degrees of hearing loss that was mostly in the mild to severe range. This high prevalence of hearing loss is consistent with data from the Hunter Outcome Survey (HOS) of MPS II patients reported by Keilmann et al. [11] [84% (n = 83)] and from another study of MPS I, II, and VI patients performed by Napiontek and Keilmann [10] [89% (n = 35)]. Among our 33 patients with hearing loss and complete PTA data, the most common classification was mixed type hearing loss in 33% (11/33). Similarly, Napiontek and Keilmann [10], Wold et al. [6], and Keilmann et al. [11] found that 51%, 71%, and 33% of their study subjects had mixed hearing loss, respectively. By cross-sectional analysis, older patients in our cohort had higher AC and BC hearing thresholds than younger patients, suggesting a worsening of hearing loss over time as expected given the progressive nature of MPS. Our finding also agrees with that of Keilmann et al. [11]. In our study, pure CHL was the most common type of hearing loss observed in younger MPS patients. With increasing age, SNHL became apparent, such that the majority of MPS patients in the older age groups exhibited mixed hearing loss or pure SNHL (Fig. 1). Interestingly, only MPS II had a significant number of patients with pure SNHL (n = 7). In other types of MPS, most cases of hearing loss were mixed or pure CHL. Our results are similar to those cited in previous reports [10,11]. However, the exact reason for the different types of hearing loss observed according to MPS type is unclear, but likely relates to the specific nature and secondary effects of the accumulated GAG substrates.
b
Bone conduction 1000 Hz (n=34)
Bone conduction 500 Hz (n=34) 80 80
r=0.539 p< 0.05
60
Mean Threshold (dB)
Mean Threshold (dB)
r=0.503 p< 0.05
40
20
0
0
10
20
30
60
40
20
0 0
40
10
Age (Years)
c
30
40
d Bone conduction 2000 Hz (n=34)
Bone conduction 4000 Hz (n=34) 80
80
60
40
20
0 0
r=0.510 p< 0.05
r=0.539 p< 0.05 Mean Threshold (dB)
Mean Threshold (dB)
20
Age (Years)
60
40
20
0 10
20
Age (Years)
30
40
0
10
20
30
40
Age (Years)
Fig. 3. Ages and means of the right and left ear hearing thresholds at 500, 1000, 2000, and 4000 Hz for bone conduction in patients with mucopolysaccharidoses (n = 34). The mean hearing thresholds for bone conduction at all four frequencies (3a–3d) increased with age (p b 0.05).
1
3
2
1
2
4
46.7 20 8.3 5 43.4 5 35 13.3 36.6 20 23.4 16.7 3.3 1.7 55 45 23.3 23.3 0 0 11.7 5 3.3 0 10 5 61.7 55 48.3 30 0 0 11.7 8.3 3.3 0 3.3 1.7 55 45 23.3 23.3 0 6.7 25 5 3.3 0 50 21.7 63.3 50 66.7 28.3 35 13.3 48.3 25 26.7 16.7 M MPS VI 6
M MPS VI 5
F MPS VI 4
MPS, mucopolysaccharidoses; AC, air conduction; BC, bone conduction.
6.3
5.2
8.5
1.9 MPS II 3
M
MPS II 2
M
4.7 10.7 17.6 23.5 15.0 16.9 11.7 20.2 7.5 12.7 8.3 14.6 MPS II 1
M
Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up Baseline Follow-up
5.9
50 21.7 63.3 50 66.7 28.3 35 25 51.7 25 28.3 23.3 6.0
50 25 78.3 60 75.0 71.7 40 13.3 48.3 46.7 26.7 16.7
Times of ventilation tube insertion Air-bone gap (dB) BC (better ear) (dB) BC (left ear) BC (right ear) AC (better ear) (dB) AC (left ear) AC (right ear) ERT duration (yr) Age at PTA (yr) PTA Gender MPS type No.
Table 2 Baseline and follow-up pure-tone audiometry (PTA) parameters of 6 patients with MPS II or MPS VI who underwent ventilation tube insertion and received enzyme replacement therapy (ERT) for 1.9 to 8.5 years.
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Although the insertion of ventilation tubes can improve CHL resulting from chronic otitis media with effusion, ventilation tubes will obviously not ameliorate SNHL, either alone or as a component of mixed hearing loss. In our results, all 6 patients with MPS II or VI improved their air-bone gap values (CHL component) after ventilation tube insertion and ERT, which has become available for the treatment of patients with some lysosomal storage diseases. Previous publications demonstrated that ERT delays the onset of hearing loss and reduces the severity of SNHL in Fabry disease [15,16]. However, for MPS, there is a paucity of literature describing the effects of ERT on hearing loss. A recent report by Brands et al. [17] describes that 2 out of 3 patients with MPS VI improved CHL after ERT, due possibly to ERT-related decrease in upper airway infections. Another study in MPS II mice suggests that although early initiation of ERT might prevent CHL, SNHL might not be prevented in the long term [18]. O'Connor et al. [19] reported that some learning, memory, and hearing deficits can be prevented in MPS VII mice if ERT is initiated early in life. In our study, all 6 patients with MPS II or VI improved or stabilized their BC values (SNHL component) after receiving ERT for 1.9 to 8.5 years (Table 2). Improvement of CHL in MPS patients receiving ERT is probably due to decrease in upper airway infections, as well as reducing middle ear effusions causing pressure on the Eustachian tube. However, it remains unclear whether SNHL has a congenital basis or is acquired secondarily to deposition of GAGs in the inner ear or central nervous system [20]. The issue concerning the effect of ERT for MPS on SNHL can be resolved only after longer follow-up. Our findings support PTA as a clinically useful method for monitoring hearing loss in MPS patients and assessing its response to ventilation tubes insertion or ERT. PTA is a well-recognized and quantitative measure for assessment of hearing loss, and all of our test results were analyzed by a single expert in PTA to avoid inter-examiner variability. There is very little published literature on the characteristics of tympanograms in MPS patients. In our study, only 30% of the tympanograms were classified as type A (normal), and 70% as types B or C. Further research is needed to determine which of the multiple mechanisms responsible for the abnormal air-bone gap and BC are most impacted by ERT. Our study has several limitations. Study patients had to be cooperative and capable of following instructions for the PTA to be performed. Consequently, patients with severe forms of MPS I–III were naturally excluded by the study design. Although auditory brainstem response is an objective test of hearing threshold that does not require the patient's cooperation, the risks of sedation for MPS patients make it difficult to use in routine clinical practice [11]. The age range of patients in our study was quite broad (4.4–34.2 years), and the number of patients was too small to draw definite conclusions about differences between MPS types. Despite these limitations, our results are consistent with those of other case series in the literature that report a high prevalence of hearing loss among MPS patients, warranting further exploration of the issue in a larger cohort.
5. Conclusion We found a high prevalence of hearing loss (85%) of varying types and severity by PTA in a cohort of 39 MPS patients unselected for auditory problems. All 6 patients with MPS II or VI showed improvements in AC, BC, and air-bone gap by PTA after receiving ventilation tube insertion and ERT for 1.9–8.5 years. PTA is a simple, accurate, and noninvasive method for measuring the type and severity of hearing loss, and we recommend screening and regular monitoring of hearing loss by PTA for patients with MPS. Findings of hearing impairment may alert clinicians and caregivers of MPS patients to take prompt appropriate counseling and intervention for their better future developments in communication, language, emotion, and behavioral regulation.
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Acknowledgments We acknowledge the participation of study patients and their families. This study was supported by the research grants from the National Science Council, Taiwan (NSC-102-2314-B-195-006 and NSC-1022314-B-195-017-MY3), and Mackay Memorial Hospital (MMH-101111 and MMH-I-S-600). We would like to express our sincere thanks to Gerald F. Cox, M.D., Ph.D. (Genzyme, a Sanofi Company) for his critical review and valuable comments, and Ms. Tsai-Feng Ho for her professional assistance in biostatistics. Conflict of interest statement The authors declare that they have no competing interests. Authors' contributions HYL performed acquisition, statistical analysis and interpretation of data, and drafting of the manuscript. SPL participated in design of the study, interpretation of the data and helped to draft the manuscript. CKC performed biochemical analyses and revised the manuscript. SCS, KSL, MRC, HCL, PCC and DMN were responsible for patient screening. All authors read and accepted the manuscript. References [1] E.F. Neufeld, J. Muenzer, The mucopolysaccharidoses, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle, B. Childs, K.W. Kinzler, B. Vogelstein (Eds.), The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York, 2001, pp. 3421–3452. [2] C.K. Chuang, S.P. Lin, Neurochemical changes and therapeutical approaches in mucopolysaccharidoses, in: Sankar Surendran, Michael Aschner, Maheep Bhatnagar (Eds.), Neurochemistry of Metabolic Diseases—Lysosomal Storage Diseases, Phenylketonuria and Canavan Disease, Transworld Research Network, Trivandrum, India, 2007, pp. 1–20. [3] H.Y. Lin, S.P. Lin, C.K. Chuang, D.M. Niu, M.R. Chen, F.J. Tsai, M.C. Chao, P.C. Chiu, S.J. Lin, L.P. Tsai, W.L. Hwu, J.L. Lin, Incidence of the mucopolysaccharidoses in Taiwan, 1984–2004, Am. J. Med. Genet. A. 149A (2009) 960–964. [4] E. Schleier, H.G. Streubel, Phoniatric aspects of children with mucopolysaccharidosis, Folia. Phoniatr. (Basel). 28 (1976) 65–72.
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