Fabry disease (FD) (OMIM 301500) is an X-linked recessive inborn error of glycosphingolipid metabolism due to the deficient activity of the lysosomal enzyme alpha-galactosidase A (EC 3.2.1.22). The deficiency of alpha-galactosidase A leads to the storage of neutral glycosphingolipids, particularly, globotriaosylceramide and galactosylceramide, in many tissues and cell types (1). The accumulation of its substrate, the globotriaosylceramide (GL-3) leads to cellular dysfunction which might in turn trigger inflammation or fibrosis or both and results in a complex, and heterogeneous disease (2). The incidence of FD, is estimated between 1/35,000 and 1/476,000 births (3, 4). Both hemizygous males and heterozygous females can be affected. Phenotypic expression in heterozygous female depends on random X inactivation and male patients usually develop a more severe form of the disease with an earlier age at onset than female patients. The manifestations of FD are progressive and multisystemic. FD induces a progressive accumulation of GL-3 in the lysosomes of endothelial, perithelial, smooth–muscle cells of blood vessels, ganglion cells, and in many cell types in the heart, kidneys, eyes, and most other tissues (5, 6). Neurological (cerebrovascular and acroparesthesia), renal, cardiac, dermatological (angiokeratoma and hypohidrosis) involvements and corneal abnormality are the major clinical manifestations in patients with the classic phenotype (2). Vascular involvement contributes to the central nervous system abnormalities (7) and vascular ischemia and lipid deposition in the perineurium may cause the peripheral nerve conduction abnormalities seen in FD (8). Patients with FD suffer from sensorineural hearing loss, with both progressive hearing impairment (microvascular mechanism) and sudden deafness (macrovascular mechanism). These patients also present peripheral vestibular deficits with dizziness and vertigo. Vascular damage seems to be involved in the pathophysiologic mechanisms of cochleo-vestibular disorders (9). A correlation of neuropathic and vascular damage with hearing loss was found in men in whom residual alpha-galactosidase A activity appears to have a protective effect against hearing loss (10). Progressive vestibular loss was found in 80% of men and 77% of women when assessed with head impulse testing (11).

Postural control, which is an inner part of many ordinary activities, is a complex sensorimotor function that requires central integration of visual, vestibular, and proprioceptive/somatosensory systems. Integration of these three inputs generates a context-specific motor response, which leads to stabilization of gaze and antigravity posture (12–15). Visual and inner ear inputs, which can be affected by FD, contribute to the postural control.

Aging and a sedentary lifestyle are accompanied by a reduction in muscle mass and strength, which may be prevented or delayed by the practice of physical and sporting activities. Becoming skilled in the sporting activities helps to improve postural performance and as a consequence, reduce the number of falls (16).

To our knowledge, only one study included postural control evaluation in FD. This study, performed in eight patients, showed normal results in all the cases except for one whose postural control was abnormal with low scores in composite and vestibular component analysis (10). Our study aimed to evaluate the impact of FD on the postural control in treated and untreated patients.

No significant differences were observed between the two groups for age, height, weight, BMI, and sex. Acroparesthesia were present in 64.3% (9 patients), 57% of them (8 patients) suffered from dizziness (accompanied by orthostatic hypotension for 28.6% [3 patients, one of them related to side effects of antihypertensive treatment (severe HCM)], 42.9% of them suffered of tinnitus (6 patients), 85.7% have a hearing loss (57% have a slight hearing loss (8/14 patients), 28.6% have a moderate hearing loss (4/14 patients), and 7.1% have an unilateral sudden hearing loss (1/14 patient); 64.3% of adult patients (9/14) were treated by enzyme replacement therapy (ERT) (Table 2). In the adult patients, 7/8 men and 5/6 women had hearing loss.

No genotype–phenotype correlation was found for hearing/balance disorders.

This study showed that balance control performance was lower in adult patients with FD patients compared with the healthy subjects. Inner ear and visual pathologies associated with the central nervous system impairments are the main factors of postural control impairments in these patients whereas no difference was observed between the two groups in the use of somesthetic input.

Fabry disease frequently leads to the inner ear dysfunctions, such as sensorineural hearing loss, sudden deafness, tinnitus, and dizziness or vertigo (20). Hearing loss in FD is due to the accumulation of GL-3 in the inner ear (21). In the mouse the loss of a-galactosidase A activity is genetically or biochemically buffered and not sufficient per se to cause an appreciable degree of hearing impairment (22). Although the alpha-galactosidase A deficient mice showed no clear hearing loss, GL-3 accumulation was demonstrated in the cochlea (21). The data demonstrate that in the mouse the loss of α-galactosidase A activity is genetically or biochemically buffered and not sufficient per se to cause an appreciable degree of hearing impairment.

Histopathologic evidence of glycosphingolipid accumulation in vascular endothelial and ganglion cells, and also atrophy of the stria and spiral ligament, might explain the otoneurologic symptoms (23).

To date, it is not known if ERT can reduce or prevent the cerebrovascular complications and hearing loss associated with FD, and it is unclear whether vertigo and tinnitus can be improved with ERT. It has been hypothesized that since migalastat is able to cross the blood–brain barrier, it might contribute in reducing the occurrence of cerebrovascular events (24).

Progressive sensorineural hearing loss can be stabilized, but not reversed (with or without treatment), but frequency of sudden hearing loss decreases during ERT compared with the frequencies observed in untreated patients (25). ERT does not appear to be a recognized therapy for sudden hearing loss. Therapeutic goals for hearing loss include stabilization of hearing loss, the possible use of hearing aids or cochlear implants to improve both hearing and patient quality of life (26).

No age effect was observed in the adult patients and one of both children (age range 10–14 y) with low posturographic performances do not present other clinical signs than postural instability.

Genotype–phenotype correlation remains controversial in FD and there is no specific data about hearing/balance disorders in term of genotype–phenotype correlation. In FD, more than 1,000 variants have been described and this high number underly the phenotype heterogeneity observed in this disease. Most of variants are “private” and confined to individual pedigrees with possible variability in phenotypic expression due to phenotype-modifying factors: i.e., genetic background, epigenetics, and environmental conditions (27, 28). One recent paper described the genotype–phenotype correlation in term of event-free but not in function of each possible clinical event, and in particular, there is no specific data about hearing/balance disorders in these patients (29). Moreover, in women patients, the phenotype depends of the genotype but also (and mainly) of the X-chromosome inactivation (30).

Patients with FD respond inappropriately to conflicting or inaccurate sensorial inputs. Vestibular alteration may explain a lower inner ear contribution in postural control (R^VEST) with lower values in postural control (CES) in patients with FD compared with the healthy subjects.

Concerning the 4 patients with vestibular hypo or areflexia, all 4 had a slight hearing loss (16 to 20 dB). The combination of vertigo and hearing loss may point to the inner ear as the origin of the disorder because of anatomic proximity of the vestibular and cochlear structures, whereas a lack of correlation between vestibular and cochlear disorders may suggest different pathophysiological mechanisms for these two structures.

Among the four patients with the vestibular disorders, two were unilateral and two were bilateral and symmetrical. Slow progressive vestibular damage, through the development of vestibular compensation mechanisms involving effective use of alternative sensory inputs, may allow the patient to experience few symptoms.

Vergence disorders and saccadic ocular pursuit contribute also to a lower postural control. Strabismus may interfere with pursuit and visual fixation and be accompanied by ophthalmic nystagmus. This oculomotor disturbance may suggest central vestibular damage. Because of the vestibuloplegic effect (antiepileptics) or the induction of nystagmus or abnormal eye movements (antiepileptics and anti-inflammatory drugs) of some of the prescribed drugs, vestibulo-ocular reflex analyses were difficult to interpret. Dizziness could be induced by inner ear toxicity (bilateral toxicity) or by the central damage.

Corneal abnormalities (cornea verticillata), neither responsible for changes in visual acuity nor causing complaints, did not decrease the weight of visual input in postural control. None of the patients with FD in our study had a visual dependency or preference.

Acroparesthesia did not cause a decrease in somesthetic afference weight.

The presence of both a decrease in visual and vestibular afference may reflect a central integration defect.

Usher syndrome, an autosomal recessive disorder, is characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia, leading to postural disability, that may have similar posturographic results to those of the FD (31).

In patients with FD, recovery in treated patients, i.e., a priori the most severe forms, would be in favor of damage to peripheral structures and a potentially curative action of the treatment. In our study, in adults, the composite score (CES) was better in treated patients than in untreated patients (76 vs. 69), as were R^SOM (0.96 vs. 0.92), R^VIS (0.86 vs. 0.79), and R^VEST (0.61 vs. 0.43), the results favoring peripheral involvement not being significant, however, due to the small size of the population.

Since the patients had comparable characteristics to the controls (in particular, age, sex, and body mass index), it was considered that if the patients showed statistically lower values than the control group, this could probably be due to their pathology. Nevertheless, based only on the average of the CES, patients with FD have values of balance (measured by dynamic posturography) close to the norms of the device, although worse than healthy individuals of the same age.

Enzyme replacement therapy treatment does not cross the blood–brain barrier and, therefore, cannot have any positive effect on the central component of the disorder.

The efficacy of the treatment would be more in favor of an effect of ERT on microvascular involvement of FD. This improvement in microvascularization could stabilize the inner ear functioning, which would require long-term follow-up to be confirmed.

This study has several limitations. The limited sample size of the population and in particular of the children should be highlighted, which limits in particular the study of the difference in symptomatology between men and women and of the impact of the type of treatment on balance and hearing. The postural control will need to be considered in the evaluation of current and future treatments for FD, whether migalastat or gene therapy. According to Palla et al., age correlated with auditory and vestibular impairments (11). The evaluation of the type of balance control recovery of vestibular disorders (i.e., recovery by compensation involving effective use of alternative sensory inputs or recovery by restoration) could require a longitudinal follow-up by vestibular and posturographic investigations, in situations of sensory conflict.

We emphasize the importance of multisensory evaluation in these patients to guide development of personalized visuo-vestibular rehabilitation techniques.

Otherwise, as we age, balance control becomes more and more dependent on vision, while this input becomes increasingly less performant. Training allows sportsmen to acquire new balance control abilities, which may differ according to the discipline practiced. Physical activity may help diminish this visual dependency by maintaining or increasing weight of proprioceptive input (32).

Physical activity practice (e.g., tai-chi, yoga) or physiotherapy can be useful to prevent balance control impairments. The beneficial effect of this training may then be transferred to daily activities.

These data suggest that understanding of specific balance control impairments in FD could contribute to propose better balance-oriented rehabilitation programs with the particular attempt of preventing falls. The multisensory evaluation of postural control helps determine the adapted modalities of visuo-vestibular rehabilitation and to evaluate in a quantifiable way its effect to improve postural stability and quality of life.

The original contributions presented in the study are included in the article/supplementary materials. Requests may be directed to the following clinicians (MD): RJ: R.JAUSSAUD@chru-nancy.fr, JD-K: j.deibener@chru-nancy.fr, FF: f.feillet@chru-nancy.fr, and PP: philippe.perrin@univ-lorraine.fr. Further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the patients/participants or patients/participants' legal guardian/next of kin.

LP-C realized posturography recordings. PK, FF, RJ, and JD-K carried out the internal medicine assessment and therapeutic management of the FD. PP managed the neuro-otological assessments. All authors contribute to the study concept and design, and contribute to the writing of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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