We have found that hearing loss contributed in a significant way to the morbidity of Fabry disease. Using age and gender-adjusted criteria for hearing loss (HL95), which is more sensitive and specific than the age and gender independent 20 dB HL threshold criterion for normal hearing, we found that Fabry disease was associated with hearing loss at all frequencies and was not limited to high frequencies. Hearing loss was more severe in males with white matter lesions, in those with peripheral neuropathy as assessed by quantitative measurement of cold perception in feet, and in those with decreased kidney function. Hearing loss in women with Fabry disease was observed later in life than in male patients (, ). Our cross-sectional findings suggest that the progression of hearing loss may be insidious or, less often, may be marked. The onset of subclinical changes in hearing can occur early in life. There was no Fabry specific configuration in the audiograms. Sensori-neural was the most common type of hearing loss. Word recognition and acoustic reflex findings were consistent with cochlear rather than retrocochlear involvement of the auditory system. Thus far, this is the largest and only cohort of patients with Fabry disease whose audiological status, peripheral neuropathy, cerebral white matter lesions and kidney function have been assessed in a quantitative manner.
This study extends prior observations of MacDermot et al. (2001b)
who conducted a questionnaire-based cross-sectional study. She described audiometrically confirmed mild-to-severe SNHL for 78% of 23 males with Fabry disease. The majority had hearing loss limited to the high frequencies (2000–3000 Hz). Self-reported hearing loss was present in 23.3% of six female obligate carriers, but was not confirmed with audiometric testing (MacDermot et al., 2001a
). More recently, auditory characteristics of individuals with Fabry disease have received more detailed and increased attention. Mid- and high-frequency SNHL has been observed in affected males with an incidence of 47–80% in two studies of 22 and 15 male patients (Germain et al., 2002
; Hajioff et al., 2003
). We observed clinically normal hearing in 70.6% of 85 males and 87.5% of 24 females when this determination was based on a four-frequency pure-tone average which may obscure hearing loss limited to the high frequencies only. However, when individual frequencies were examined and age and gender corrections were taken into consideration (HL95
), the prevalence of hearing loss in our group was as high as 86% in males aged 31–58 years and 45% in females aged 31–72 years.
Many individuals are unaware of their diminished hearing as evidenced by a self-report of hearing loss in 41% (n = 61) of a group with audiometrically confirmed hearing loss in 78% (MacDermot et al., 2001b
). In other cases, individuals are acutely aware of auditory change, especially when the onset is abrupt. While sudden onset of SNHL was reported by 7 (32%) of 22 subjects reported by Germain et al. (2002)
, we observed sudden hearing loss in only 10 (11.8%) of 85 males of our group.
Evaluation of hearing ability in individuals with Fabry disease must take into consideration other systemic disease manifestations. In males with HL95
, we observed decreased kidney function (determined as a continuous measurement of BUN and creatinine) as compared with those who did not have HL95
. This extends the findings of two reports in which glomerular filtration rate correlated with hearing status in cohorts of 22 and 15 affected males (Germain et al., 2002
; Hajioff et al., 2003
In this study, males with HL95
had more severe cerebrovascular manifestations as quantified by white matter lesion load than those without HL95
. This extends the report by Germain et al. (2002)
in which males with evidence of cerebrovascular disease had higher average pure-tone thresholds than those without evidence of cerebrovascular disease.
Tinnitus is a frequent symptom in patients with Fabry disease and was reported by 27–38% of hemizygous males (MacDermot et al., 2001b
; Germain et al., 2002
) and 25% of female carriers (MacDermot et al., 2001a
). Our data suggest that tinnitus may be present in a larger percentage (41.3% males, 62.5% females). This difference may reflect phenotypic heterogeneity, differences in age or differences in the query methods used to assess the presence of tinnitus. In an Australian population based sample which was older than our cohort (n = 2015, age 55–99 years), the prevalence of tinnitus was 30.3% (Sindhusake et al., 2003
The mechanisms of hearing loss in Fabry disease are not precisely understood. Abnormal blood flow (Moore et al., 2002
), altered blood vessel properties (Altarescu et al., 2001a
) or abnormal blood composition (DeGraba et al., 2000
) may contribute to microvascular damage resulting in cochlear dysfunction. In a temporal bone histopathological report of two Fabry patients with bilateral sloping SNHL, Schachern et al. (1989)
observed cytoplasmic vacuolization of the endothelial cells of blood vessels in the modiolus, a reduced number of spiral ganglia of the auditory nerve, ballooning of Scarpa ganglia of the vestibular nerve, strial and spiral ligament atrophy, and hair cell loss in the cochlear basal turns. It is possible that progressive storage of Gb3
in the auditory sensory organ itself might contribute to the pathogenesis of hearing loss. However, these histopathological findings more likely suggest that in Fabry disease the accumulation of Gb3 in the audiovestibular nerve ganglia and vascular endothelium of the cochlear vessels results in chronic microvascular insufficiency and permanent progressive cochlear neuronal and sensory organ damage. Sudden hearing loss reported by >10% of our cohort of Fabry patients is most likely a manifestation of an acute microvascular event. In this study we relate the quantitative state of organs remote from the ear (renal, cerebrovascular and neuropathic) to hearing status suggesting a parallel impact of vascular and neuropathic dysfunction on these systems.
Our observations indicate that detectable hearing loss starts in the second and fourth decades of life for Fabry male and females, respectively. These auditory deficits affect all frequencies, but the high frequencies deteriorate more rapidly with increasing age. Because auditory deficits are common yet often underdiagnosed, we recommend that all patients with a diagnosis of Fabry disease should undergo annual audiological evaluation to monitor their hearing status starting their second decades for males and third decades for females, especially in the presence of renal dysfunction and cerebral vascular insufficiency. In cases of sudden hearing loss, the patients with Fabry disease should immediately undergo otolaryngological and audiological evaluation since a prompt medical intervention might be beneficial in restoring auditory function in some cases of sudden SNHL as suggested by a retrospective study in 75 patients with idiopathic hearing loss by Slattery (Slattery et al., 2005
The conclusions of this study are limited by its retrospective design and the fact that patients were seen as adolescents or adults at various ages. We cannot exclude selection bias. Patients were seen on natural history and enzyme replacement therapy protocols that were not designed to study auditory involvement in Fabry disease. Some patients were first studied prior to the initiation of enzyme replacement and some subsequently. The patients described in this study were not randomly selected, but referred to the NIH by their physicians or themselves. Initially the audiological evaluations were not indicated for research but for clinical reasons after an increasing number of patients with auditory complaints raised our attention. We consequently directed our efforts towards a broad and thorough auditory examination of our available study population, which is based on the chart review of 189 audiograms in 109 patients. Last, the interpretation of findings in patients with residual enzyme activity above 1.5% is based on a small group of patients. A large, prospective study with both male and female patients with Fabry disease should be helpful to further elucidate the auditory manifestations of Fabry disease.