4.1.1 Neuropathic pain, pain related disability, and depression
Peripheral neuropathy in patients with Fabry disease is axon length-dependent and characterized by selective involvement of small fibers 31,46,52, and neuropathic pain is the earliest symptom appeared in most Fabry patients.
Although we screened only a limited number of children, there were no differences in the prevalence of neuropathic pain between children and adults, which was also reported by another group 40. Compared with adults, the children had less pain and none of them showed indication of depression. In adult patients, no difference of pain severity and pain related disability was found between older and younger male patients. While female patients younger than 40 years showed less pain, pain related daily disability, and depression than the corresponding male patients and female patients older than 40 years;
such differences disappeared in older female patients. Contrary to the traditional view of females as carriers, female patients experienced intense disease-related pain and pain produced comparable distress, and seemed to be age-related, although such correlation was not statistically established.
Although male patients had higher pain score, the interference of pain with daily life and mood was more obvious in female patients, which is corresponding with other reports 40,63.
GFR did not significantly affect pain in male patients. In women, correlations between GFR and the disability severity (p=0.031, r=-0.332), and depression symptoms (p=0.042, r=-0.305) were found, which indicate that renal function may play a role of pain related depression in female patients. Although pain perception is dependent on small fiber involvement, our study could not detect any correlation between pain, QST profile, and IENFD in any group of patients.
4.1.2 QST and small fiber function
A significantly increased cold detection threshold (CDT, indicating loss of sensory function for cold stimuli) was found in male patients older and younger than 40 years, while unmyelinated C-fiber -mediated warm detection thresholds were often within the normal range. That cold perception is more frequently and severely impaired than warm perception in male patients was also reported previously 31,64,65. We also found correlations between CDT and distal IENFD both in male (p=0.04, r= 0.329) and female patients (p=0.04, r= 0.413). No other correlation between QST and IENFD was found. Based on these findings, there might be a more pronounced loss of Aδ-fibers than C-fibers in Fabry disease. In our study, PGP 9.5 antibody was used. It is a polyclonal panaxonal marker that stains both Aδ- and C-fibers, and currently the most commonly used marker for IENFD studies. Although CGRP and Substance P are specific antigens for C-fibers 66,67, the fact that many patients had only very low IENFD or even no innervation prevented us from specifying the fiber losses. We speculate that the GL-3 deposits in the cell bodies and axons of A fibers and in the adaxonal cytoplasm of the surrounding Schwann cells might lead to more severe functional loss than the unmyelinated axons of C fibers 46,68.
Besides increased CDT, significantly increased thermal sensory limen (TSL) and decreased vibration detection threshold (VDT) were found in male patients younger than 40 years, which were also signs indicating loss of sensory function of C- and Aß- fibers respectively. This finding indicates that sensory function disturbance developed when patients were still young and maybe due to the fact that most thermal and mechanical thresholds increased with age 58, the differences of sensory function and the corresponding QST values might not be obvious at an older age.
In male groups, compared to patients with relatively normal renal function,
patients with pathological renal function had increased dynamic mechanical allodynia (DMA) indicating a peripheral and central sensitization. Dynamic mechanical allodynia is the pain due to a light moving mechanical stimulus, and occurs in subgroups of patients with peripheral or central neuropathic pain.
Both peripheral and central nervous system mechanisms have been implicated in the generation of DMA. In subgroups of patients with post-herpetic neuralgia peripheral sensitization of nociceptive afferents have been suggested as a basis for dynamic mechanical allodynia 69, while Baron et al. argue that this symptom may be due to secondary changes in the central nervous system processing that might strengthen the synaptic ties between A beta-fibers and central nociceptive pathways and not necessarily related to ongoing nociceptive C-fiber input 70. In our study, there was more severe small fiber loss in patients with pathological renal function. We hypothesize that more severely damaged small fibers may indicate more disturbed function or damage of the neurons both peripherally and centrally, so besides the small fiber dysfunction, the secondary central hyperexcitability might contribute to the DMA in patients with pathological renal function.
Of 32 adult female patients, 29 had abnormal QST values, but only 4 patients had reduced CDT. A recent study reported that 25% of female patients had abnormal CDT in the foot 51, the small sample (n=12) of their study may count for this discrepancy. Generally, although female patients also suffer from severe neuropathic pain, especially in older group, the small nerve fibers are less affected, which supports our finding that there is a lack of correlation between pain and QST profile in Fabry patients. Patients with pathological renal function seemed to have decreased thermal detection threshold compared to patients with normal renal function, although not statistically significant, which also in accord with our finding that female patients are less affected concerning small fiber function.
4.1.3 Skin innervation (IENFD) in FD
Since standard nerve-conduction studies and large nerve biopsy results are typically normal in small-fiber neuropathy, the investigation of intraepidermal nerve fibers is widely used for the diagnosis of small-fiber neuropathy including FD related neuropathy 53,71,72. Compared to our laboratory’s normal values for Th12 and the lower leg, the intraepidermal innervation density was significantly reduced in male patients (18.0 +/- 8.8 fibers/mm proximally and 2.2+/-2.8 fibers/mm distally), and mildly reduced in female patients (26.2 +/- 9.9 fibers/mm proximally and 6.3 +/- 4.3 fibers/mm distally). In male patients a severe loss of intraepidermal innervation at the ankle but less severe at the distal thigh has been described 52,53,64, which is in line with our findings. The reduced density of the subepidermal nerve plexus was also more frequent in male patients. Unlike the other vital organ involvement which affected females as severely as males in the groups older than forty years, the small fiber loss is more severe in males than in females in all age groups. Although female patients also suffer from severe neuropathic pain, especially in the older group, the loss of small nerve fibers was less severe, which is consistent with our findings in the QST profile and the lack of correlation between pain and IENFD in Fabry patients. However, strong correlations between age and distal but not proximal IENFD were found both in male (p=0.000, r=-0.726) and female patients (p=0.001, r=-0.688), which is also the case with healthy people 73,74 and is consistent with the fact that most thermal and mechanical thresholds increased with age 58.
In male patients there was a strong correlation between GFR and distal IENFD (p=0.000, r=0.798). Such a correlation was not found in the female group, the possible reason is that in the 19 female patients who had the skin biopsies, only three had pathological renal function. Clinical trials have shown that patients with impaired renal function at baseline have a less favorable outcome and may
develop renal progression despite treatment with ERT 34. Guidelines for the treatment of Fabry disease are being developed but currently not uniformly applied 75, and the initiation of ERT is based mainly on the clinical course of the disease, in particular the vital organ events 76. Our findings indicate that combined together, GFR and IENFD may serve as useful items in the decision when to start ERT and other comprehensive treatment to prevent the irreversible nerve damage.
Strong correlations between age and distal IENFD were found both in male (p<0.001, r=-0.726) and female patients (p<0.001, r=-0.688). In healthy people, most thermal and mechanical thresholds increased with age 58, while the distal IENFD decreased with age 73,74. Such trends were also found in our Fabry patients.