The correlation of small fiber neuropathy with pain intensity and age in patients with Fabry's disease: A cross sectional study within a large Taiwanese family

Abstract

Background: The relationships among small fiber neuropathy, age, sex and pain intensity in the context of Fabry's disease remain unclear. We aim to study the correlations of small fiber neuropathy, age, sex and pain intensity in Fabry patients.

Methods: We evaluated C-fiber function by recording the withdrawal latencies to painful heat stimulus (WLPHS) when each subject's right hand was immersed in a 50 °C hot water bath and correlated this parameter with the patient's perceived pain intensity and quality of life assessed by the short-form McGill Pain Questionnaire (SF-MPQ) in a large Taiwanese Fabry family and normal controls.

Results: Male Fabry patients showed a significantly increased WLPHS compared to that of normal controls. Furthermore, male Fabry patients showed a positive correlation of increased WLPHS with patient age. The SF-MPQ of male Fabry patients showed a bell distribution with age, and maximal pain scores were detected between the ages of the early 20s and late 40s. In contrast, the female Fabry patients had variable associations of WLPHS and SF-MPQ with age.

Conclusions: We proposed a probable mechanism by which globotriaosylceramide (Gb3) or globotriaosylsphingosine (lyso-Gb3) is gradually deposited into the small nerve bundles with increasing age, which induces continuous damage and produces injury discharges to sustain neuropathic pain in young male Fabry patients. However, once the small fibers are reduced to a certain degree, they no longer produce enough noxious discharges to sustain neuropathic pains in older male Fabry patients, which leads these patients to have lower SF-MPQ scores. In contrast, female Fabry patients had less and variable small fiber damage, pain intensity and clinical signs/symptoms.

Keywords: Acroparesthesia; Fabry's disease; Neuropathic pain; Small fiber neuropathy; Unmyelinated fiber.

Fig. 1

Pedigree of the large Taiwanese Fabry family in this study.

Fig. 2

Evaluation of the pain severity and quality of life of Fabry patients by the Short Form McGill Pain Questionnaire (SF-MPQ). On this scale, higher scores indicate greater pain. (A) In male Fabry patients (□), there was a tendency of increased pain severity with age from the teens to late 40s, and maximal pain scores were noted between the ages of the early 20s to late 40s. The pain severity gradually declined after the age of 48 years. (B) However, there was variability in the degree of pain associated with age in female Fabry patients (○).

Fig. 3

(A and B) Withdrawal latencies to painful heat stimuli (WLPHS) in male Fabry patients (□) showed markedly increased withdrawal latencies with age compared with the latencies of controls (■) (70.50 ± 37.13 s vs 8.23 ± 4.85 s multiple linear regression, ∗∗p < 0.01, Mann–Whitney test, ∗∗p < 0.01). There was a positive linear relationship between WLPHS and age in male Fabry patients (simple linear regression, r² = 0.55) but not in male normal controls (simple linear regression, r² = 0.19). (C and D). In contrast, female Fabry patients (○) had variable withdrawal latencies but generally had mildly increased withdrawal latencies compared with those of controls (●) (14.38 ± 9.58 s vs 8.15 ± 6.39 s multiple linear regression, p = 0.70, Mann–Whitney test, p = 0.06, ns: not significant). There was a weak positive linear relationship between WLPHS and age in female normal controls (simple linear regression. r² = 0.38) but not in female Fabry patients (simple linear regression. r² = 0.14). (E and F) Male Fabry patients had significantly increased withdrawal latencies with age compared with female Fabry patients (multiple linear regression, ∗p < 0.05, unpaired t test, ∗∗p < 0.01). The black solid lines represent simple linear regression of WLPHS and age in male and female Fabry patients, respectively. The black dotted lines represent simple linear regression of WLPHS and age in male and female normal controls, respectively.

Fig. 4

Relationship between SF-MPQ and WLPHS in male Fabry patients. The WLPHS indicated that C-fiber dysfunction increased with age. However, the SF-MPQ, which indicated subjective pain sensation, had a bell shape distribution with age. We hypothesized that the damaged C-fibers cannot sustain peripheral and central sensitization in old age, which leads older patients to have lower SF-MPQ scores. (□): Withdrawal latencies to painful heat stimuli (WLPHS) in male Fabry patients (■): Short Form McGill Pain Questionnaire (SF-MPQ) in male Fabry patients. The black solid line represents the simple linear regression of WLPHS and age in male Fabry patients. The dashed line represents the bell shape distribution of the SF-MPQ with age in male Fabry patients.