This study presents the first evidence of the high incidence of progressive hearing loss, sudden deafness, and tinnitus aurium in a cohort of 22 male patients affected with Fabry disease (FD), an orphan lysosomal storage disease. Fifty-two percent of the patients complained of a progressive (n = 5) or sudden (n = 7) deafness, and 6 patients had tinnitus aurium. Approximately 82% of all patients had at least two auditory thresholds above the 95th percentile for frequencies varying between 0.5 and 4 kHz, or above the 90th percentile for the 8 kHz frequency. All cases of deafness were sensorineural hearing losses.
The origin and the mechanisms of deafness probably involve the inner ear. In our study, no patient had conductive hearing loss, and all patients had type A tympanograms, in favor of normal middle ear mobility and pressure. Distortion products and transient-evoked otoacoustic emissions responses were consistent with the degree of hearing loss (i.e., absence of emissions in subjects with auditory thresholds above 30 dB hearing loss (HL) in the range of 1 to 4 kHz). In this study, ABR audiometry did not reveal any abnormality in intervals between waves I and V, and waves III and V. In the literature, clinical histories, audiometric results, and temporal histopathology were described [4
] for two patients (48- and 59-year-old men) with FD [6
]. Both patients demonstrated a bilateral sloping sensorineural hearing loss. Neuropathologic findings of the inner ear were major and identical. Evidence of glycosphingolipid accumulation in the ear in vascular endothelial cells, and in various ganglion cells, atrophy of the stria vascularis
and the spiral ligament in all cochlear turns was observed in both cases. The authors concluded that hearing loss was caused by accumulation of glycosphingolipids within the stria vascularis
and ganglion cells.
There could also be an endothelial or vascular component to deafness in FD patients, due to capillary wall hypertrophy, encroaching the lumen. Indeed, globotriaosylceramide (Gb3) accumulates in all cells of the body but has some key target sites of pathology, and deposition of glycosphingolipids occurs widely in the lysosomes of vascular endothelial and smooth-muscle cells [5
]. Therefore, hearing loss and more specifically sudden deafness could also be potentially caused by vascular mechanisms due to the accumulation of glycosphingolipids within lysosomes of endothelial and smooth muscle cells leading to progressive narrowing, ischaemia, and frank occlusion in the vessels feeding the cochlea.
Finally, although intracellular Gb3 storage represents the initial insult to the cells, it is possible that a cascade of pathological mechanisms are involved in the development of disease-related complications, as suggested by recent studies which revealed an imbalance in vascular reactivity and the propensity for a pro-thrombotic state among patients with FD [14
Interestingly, we found a correlation between kidney and cochlear involvement in our population. Most patients with hearing loss had a decreased glomerular filtration rate. Among our patients, 9 had severe renal insufficiency necessitating dialysis or kidney transplantation, and the responsibility of hemodialysis and renal transplant in the occurrence of hearing loss can be questioned. However, recent studies seem to indicate that neither dialysis nor renal transplant are the main cause of observed deafness in end-stage renal disease patients [15
]. In our patients, the hearing loss was present in most cases before dialysis or transplant. However, it is still possible that both dialysis and transplantation could contribute to worsen a pre-existing hearing impairment. Cochlear lesions have been described in association with kidney insufficiency in various pathological situations, and pathophysiologic similarities have been observed between the kidney and the cochlea. One illustrating example is the common nephrotoxic and ototoxic component of various drugs or medicines (aminoglycosides, cisplatinum, furosemide...). For aminoglycosides the mechanism, although complex, seems to be related to lysosomal dysfunction. Aminoglycosides enter proximal epithelial cells of the kidney through endocytic vesicles which subsequently fuse with lysosomes. Aminoglycosides that resist to degradation can induce an alteration of the lysosomal phospholipase, a modified permeability of lysosomal membranes and a reduction in catabolism of renal proteins inducing phospholipidosis. A decrease of mitochondrial oxidative phosphorylation, an inhibition of the lysosomal membrane Na/K+ ATPase and the generation of superoxide anion and hydrogen peroxide were also observed. Similar mechanisms have been observed in the inner ear, specifically for outer hair cells [16
] leading to sensorineural deafness, mainly on high tone frequencies. In FD, the lysosomal storage could trigger a similar mechanism with the epithelial cells of the kidney and the outer hair cells representing a key target site of pathology. Furosemide has also both ototoxic and nephrotoxic effects, inhibiting Na/K/Cl channels which are present on the renal tubular cells as well as the cells of the stria vascularis.
Both examples appear interesting with respect to the clinical manifestations of FD, also affecting both the kidney and cochlea. Could similarities between the stria vascularis
of the ear and the tubular cells of the kidney explain cochlear and kidney manifestations in FD through a common pathophysiology? Could ENT investigations allow to predict an evolution to end-stage renal disease in patients demonstrating hearing loss? These hypothesis necessitate further studies, among which examinations of histopathological specimens of the cochlea in patients affected with FD. Such histopathological pieces are however extremely rare, due to the rapid deterioration of cochlea after death, and only 2 patients have been described in the literature [6
]. Histopathological studies of the cochlea obtained from the knock-out mouse models of FD could also potentially provide interesting data [17
FD is a multisystem disorder associated with a wide variability in clinical expression and one of the most devastating features of FD are strokes or cerebrovascular accidents (CVA). In one study, the mean age at onset of cerebrovascular complications was 33.8 years and the commonest anatomical localisation for CVA was the vertebrobasilar territory with a high recurrence rate and reduced life expectancy [19
]. Another study of 33 males reported the incidence of cerebrovascular complications as 24%, with lesions localised to both the carotid and vertebrobasilar territories and occurring mostly before the age of 40 [20
]. We observed a positive correlation between hearing loss and cerebrovascular accidents in our cohort of FD patients, further emphasising the importance of the vascular component as a likely mechanism for the occurrence of deafness in FD.
Data are available from several cohort studies, documenting a high frequency of left ventricular hypertrophy (LVH), concentric apical hypertrophy, and intraventricular septum thickening in FD [21
]. Age-related progression of echocardiographic LVH changes, correlating with disease severity was reported in a cohort of young males, aged 14–43 years (n = 23) [24
]. Out of the 22 patients evaluated in the present study, 12 (55%) had LVH. Although we found a trend between cochlear involvement and LVH, statistical significance was not reached. Previous histopathological studies have shown that glycosphingolipid storage occurs in both cardiac capillaries and cardiomyocytes in classic FD. However, LVH is observed not only in the classic form but also in the cardiac variant of FD in which, interestingly, there is no storage in the vascular endothelium [5
]. Therefore, the absence of statistically significant correlation between hearing loss and LVH could be in favour of different pathological mechanisms for these two lesions. Endothelial storage and dysfunction could be an important feature of the cochlear lesions, while LVH could be more related to storage in cardiomyocytes and subsequent dysfunction of metabolic pathways rather than to vascular involvement. However, our statistical analysis was limited to LVH (defined as septal wall thickness ≥ 13 mm or posterior wall thickness ≥ 13 mm, or cardiac mass > 130 g/m2
) assessed by echocardiography or cardiac MRI. It could be interesting to search whether a positive correlation between heart symptoms and hearing loss would appear when all cardiac manifestations including ECG modifications such as short PR interval, conduction abnormalities and rhythm disturbances are considered in the analysis.
Advances in the application of molecular genetic techniques have enabled development of directed protein therapies in Fabry disease. To a large extent, this milestone has resulted in a shift in the management paradigm offered to patients from an approach that relied on predictive genetic counseling and palliative care to the genuine possibility of offering early diagnosis and active intervention. However, the heterogeneity of clinical expression, the paucity of reliable markers and the uncertainty a priori
of being able to reverse the disease create a problem in the selection of the appropriate endpoints to evaluate the efficacy of therapeutic interventions [7
]. Similarly, the decision to initiate enzyme replacement therapy (ERT) in asymptomatic patients is confounded by the variability of the phenotype and the absence of surrogate markers that reliably predict the pattern of organ involvement and disease severity. With this respect, our extensive evaluation of cochlear functions in a cohort of male patients affected with FD, demonstrating the high incidence of both progressive and sudden deafness, should prove useful in delineating the importance of cochlear lesions in the natural history of FD. We recommend an audiogram to be systematically performed in each FD patient prior to initiate ERT. Indeed, it could possibly serve as an additional endpoint for establishing whether enzyme replacement is effective in reducing or eliminating the incidence of FD-related hearing impairment. However, in view of the various possible mechanisms of hearing loss in FD, palliative measures may continue to be important in conjunction with ERT to achieve complete patient response or disease control, specifically if outer haired cells are destroyed.
Finally, we have also demonstrated that high tone deafness, usually not clinically significant but definitely confirmed by audiograms, was present at young age in hemizygotes. This is an important consideration because it is likely that delayed treatment, at a stage when advanced tissue changes (e.g., cochlear sclerosis or outer cells death) are established may not lead to full recovery and represent persistent sources of morbidity. This data further emphasize that early therapeutic intervention should offer increased possibilities of mitigating the disease process in Fabry disease [25