Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study

Abstract

Background: Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP).

Methods: In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function.

Results: All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients.

Conclusion: Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.

Figure 1

Sensory profile of Fabry patients. The bar graphs show the z-score sensory profiles of quantitative sensory testing (QST) at the left dorsal foot in Fabry patients compared to healthy controls. Healthy controls are represented by the black zero line. Z-scores < 0 display loss of function, z-scores >0 show gain of function. a) Male Fabry patients have elevated detection thresholds for cold and warm (CDT, WDT), while the thermal sensory limen (TSL) for changing temperatures and the vibration detection threshold (VDT) was not different from controls. b) Female Fabry patients do not differ from female controls except for slightly elevated WDT. *p < 0.05, **p < 0.01.

Figure 2

Pain-related evoked potentials from face, hands, and feet stratified for gender. Pain-related evoked potentials (PREP) in patients with Fabry disease and in healthy controls. a, b, c: N1 and P1 latencies of Fabry patients are not different from controls after eliciting PREP at the face, hand, and feet. d, e, f: Peak-to-peak amplitudes (PPA) of PREP are reduced in male Fabry patients when PREP is elicited at the face, the hands, or the feet. *p < 0.05, **p < 0.01.

Figure 3

Pain-related evoked potential amplitudes from face, hands, and feet stratified for gender and disease severity. Boxplots show the comparison of PREP PPA stratified for renal function. Male Fabry patients with impaired renal function have reduced PREP PPA after eliciting PREP from face (p = 0.012, a), hands (p = 0.007, b), and feet (p = 0.007, c). *p < 0.05, **p < 0.01.

Figure 4

Correlations of sensory profile and nerve fiber density with pain-related evoked potential amplitudes. Scatter plots show correlations between PREP peak-to-peak-amplitudes (PPA) recoded after stimulation at the feet and QST parameters (warm detection threshold, WDT; cold detection threshold, CDT; thermal sensory limen, TSL; vibration detection threshold, VDT). a) PREP PPA correlated positively with CDT in male (correlation coefficient: 0.564, p = 0.002) and female Fabry patients (correlation coefficient: 0.340, p = 0.034). b) PREP PPA correlated positively with WDT only in male Fabry patients (correlation coefficient: 0.390, p = 0.04). c, d) TSL and VDT did not correlate with PREP PPA in either gender. e) Distal IEFND did not correlate with PREP PPA obtained after stimulation at the foot.