Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

Abstract

BackgroundFabry Disease (FD) is characterized by globotriaosylceramide-3 (Gb3) accumulation in several tissues and a small fibre neuropathy (SFN), however the underlying mechanisms are poorly known. This study aimed to: 1) ascertain the presence of Gb3 deposits in skin samples, by an immunofluorescence method collected from FD patients with classical GLA mutations or late-onset FD variants or GLA polymorphisms; 2) correlate skin GB3 deposits with skin innervation.Methodswe studied 52 genetically-defined FD patients (32 with classical GLA mutations and 20 with late-onset variants or GLA polymorphisms), 15 patients with SFN associated with a specific cause and 22 healthy controls. Subjects underwent skin biopsy to evaluate Gb3 deposits and epi-dermal innervation.ResultsSkin Gb3 deposits were found in all FD patients with classical GLA mutations but never in FD patients with late-onset variants or GLA polymorphisms or in patients with SFN and healthy controls. Abnormal deposits were found inside different skin structures but never inside axons. FD patients with GB3 deposits showed lower skin innervation than FD patients with late-onset variants or polymorphisms.Conclusions1) Skin Gb3 deposits are specific to FD patients with classical GLA mutations; 2) Gb3 deposits were associated with lower skin innervation but they were not found inside axons, suggesting an indirect damage on peripheral small fibre innervation.

Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model

“…decreased and scattered pattern of neuronal terminations in the frontal skin paw of α-Gal A −/0 mice, in comparison with their α-Gal A +/0 littermates 51. This finding mirrors the decrease in neuronal terminations marked by PGP9.5 in skin biopsies of human patients with small fiber 11,55. Based on these findings, we next investigated the density of nerve fibers entering the colonic mucosa, through IFanalysis of PGP9.5-positive nerve fibers on transverse floating sections of 8-to 10-week-old, 16-to 20-week-old, and 12-month-old α-Gal A +/0 and α-Gal A −/0 male mice colon.…”

“…Pain can be manifested as episodic crisis with pain attacks originating in the extremities that can last for several days or even weeks, or chronic pain, characterized by burning and tingling paresthesia. In line with this, FD patients show reduced intra‐epidermal nerve fiber density and impaired thermal perception . Several lines of evidence indicate that the origin of the peripheral pain presumably lies in the accumulation of Gb3 within peripheral nerves and/or dorsal root ganglion (DRG) that might lead to degeneration of small sensory fibers .…”

“…In line with this, FD patients show reduced intra-epidermal nerve fiber density and impaired thermal perception. [9][10][11] Several lines of evidence indicate that the origin of the peripheral pain presumably lies in the accumulation of Gb3 within peripheral nerves and/or dorsal root ganglion (DRG) that might lead to degeneration of small sensory fibers. 3,12 In this regard, it has been recently demonstrated that the α-Gal A (−/0) hemizygous male mice (FD mouse model), which share many symptoms with FD patients, present molecular and structural changes in peripheral nerves which underlie pain and sensory-perceptual alterations such as heat/cold hyperalgesia and mechano-hyperalgesia.…”

The GALA project: practical recommendations for the use of migalastat in clinical practice on the basis of a structured survey among Italian experts

“…Neuropathic pain is probably related to progressive reduction in the density of small myelinated and unmyelinated C fibers in the peripheral somatic and autonomic nervous system, while hypohidrosis is mainly due to both small fiber neuropathy and sweat gland tubules GL3 deposits [21]. Some studies suggest a benefit of ERT on neuropathic pain [47][48][49][50]. In Phase III ATTRACT study, patients in migalastat group or in ERT group had stable and comparable scores on the Brief Pain Inventory-Short Form during the study period [15].. Clinical evidence for an improvement of acroparesthesiae and hearing loss is still wanted.…”

<p>Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype&ndash;phenotype correlations</p>

“…Accumulation of undegraded AGAL substrates in primarily affected organs constitute the major evidence of FD. The abnormal intracellular storage of Gb3 can be either confirmed or suspected from histological, immunohistological, or ultrastructural examination of relevant tissue samples, with kidney,32,48 skin,49 and heart50 biopsies having been the most frequently used in the clinics. Whatever the tissue sample, the presence of extensive Gb3 deposits in vascular endothelial cells is considered a marker of severe AGAL deficiency 2,9,49…”