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

Date Published: July 3, 2017

Publisher: Public Library of Science

Author(s): Rocco Liguori, Alex Incensi, Silvia de Pasqua, Renzo Mignani, Enrico Fileccia, Marisa Santostefano, Elena Biagini, Claudio Rapezzi, Silvia Palmieri, Ilaria Romani, Walter Borsini, Alessandro Burlina, Roberto Bombardi, Marco Caprini, Patrizia Avoni, Vincenzo Donadio, Rayaz Ahmed Malik.

http://doi.org/10.1371/journal.pone.0180581

Abstract

Fabry 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.

we 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.

Skin 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.

1) 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.

Partial Text

Fabry Disease (FD) is a rare x-linked disorder[1] characterized by an abnormal function of the lysosomal enzyme alpha-galactosidase A (GLA)[2,3], involved in the cleavage of galactose residuals of globotriaosylceramide-3 (Gb3)[4]. As a consequence, Gb3 starts to accumulate within lysosomes of several tissues involving blood vessels, kidneys, nervous system and heart, as well as dermal fibroblasts[5–8], accounting for FD’s clinical features[9,10] mainly including small fibre neuropathy (SFN)[11], stroke, and renal and cardiac dysfunctions[12]. SFN is mainly responsible for paraesthesias of extremities, hypohydrosis, abdominal pain and diarrhoea[5,11,12] often beginning in childhood with progressive severity throughout life. The available enzyme replacement therapy (ERT) started early before the appearance of organ failure may decrease the pathological impact of this disorder[5].

We studied 52 genetically-defined FD patients including 14 males and 38 females (36±15 vs 45±14 years; p = 0.05) who belong to 26 different families (Tables 1 and 2). Patients were recruited in different FD tertiary centres and evaluated at IRCCS Institute of Neurological Sciences of Bologna. They included 32 patients with classical GLA mutations; 17 patients with late-onset FD variants and 3 patients with GLA polymorphisms, subsequently named as non-classical mutations group (Table 2). To test the specificity of skin Gb3 deposits in FD patients, Gb3 were also searched in 15 patients with SFN associated with specific causes (i.e. 4 patients with diabetes, 3 with Sjogren disease, 2 with hepatitis C, 3 with Parkinson’s disease and 3 with amyotrophic lateral sclerosis) and 22 healthy controls. SFN patients and controls were sex- (5M:10F and 10M:12F respectively) and age-matched (49±8 and 46±18) compared to FD patients (Table 1).

The main conclusions of our study were: 1) skin Gb3 deposits are specific to FD patients with classical GLA mutations; and 2) Gb3 deposits were associated with lower skin innervation but they were not found inside the axons, suggesting an indirect damage on peripheral small fibre innervation.

 

Source:

http://doi.org/10.1371/journal.pone.0180581

 

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