Idiopathic small fiber neuropathy: phenotype, etiologies, and the search for fabry disease

Abstract

Background and purpose: The etiology of small fiber neuropathy (SFN) often remains unclear. Since SFN may be the only symptom of late-onset Fabry disease, it may be underdiagnosed in patients with idiopathic polyneuropathy. We aimed to uncover the etiological causes of seemingly idiopathic SFN by applying a focused investigatory procedure, to describe the clinical phenotype of true idiopathic SFN, and to elucidate the possible prevalence of late-onset Fabry disease in these patients.

Methods: Forty-seven adults younger than 60 years with seemingly idiopathic pure or predominantly small fiber sensory neuropathy underwent a standardized focused etiological and clinical investigation. The patients deemed to have true idiopathic SFN underwent genetic analysis of the alpha-galactosidase A gene (GLA) that encodes the enzyme alpha-galactosidase A (Fabry disease).

Results: The following etiologies were identified in 12 patients: impaired glucose tolerance (58.3%), diabetes mellitus (16.6%), alcohol abuse (8.3%), mitochondrial disease (8.3%), and hereditary neuropathy (8.3%). Genetic alterations of unknown clinical significance in GLA were detected in 6 of the 29 patients with true idiopathic SFN, but this rate did not differ significantly from that in healthy controls (n=203). None of the patients with genetic alterations in GLA had significant biochemical abnormalities simultaneously in blood, urine, and skin tissue.

Conclusions: A focused investigation may aid in uncovering further etiological factors in patients with seemingly idiopathic SFN, such as impaired glucose tolerance. However, idiopathic SFN in young to middle-aged Swedish patients does not seem to be due to late-onset Fabry disease.

Keywords: Fabry disease; etiology; idiopathic; impaired glucose tolerance; small fiber neuropathy.

Fig. 1

Flow chart of excluded and included patients. In total, 213 patients with suspected SFN were identified originally. The numbers of patients excluded and the reasons for exclusion are noted in the figure. Ultimately, 29 patients judged to have an idiopathic SFN were included. The proportion of idiopathic SFN using the basic level of investigation/screening was 25% [33/133 (33=29 included patients plus 4 patients who declined participation in the genetic study, and 133=88 in exclusion group A plus 12 in exclusion group B plus 33)]. ^*Exclusion group A, ^†Exclusion group B. SFN: small fiber neuropathy.