The importance of a multidisciplinary approach in two tricky cases: the perfect match for Fabry disease

Abstract

Anderson-Fabry disease (AFD) is a multisystem X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A (α-Gal A). This deficiency results in the intracellular accumulation of glycosphingolipids, primarily uncleaved globotriaosylceramide (Gb3) and its deacylated form, lyso-globotriaosylceramide (Lyso-Gb3), leading to progressive organ damage and functional impairment. The diagnostic evaluation for AFD involves clinical assessment and family history, supported by biochemical testing (α-Gal A enzyme activity and Lyso-Gb3 levels) and genetic analysis of the GLA gene. In cases of unexplained renal impairment or when genetic analysis is inconclusive, kidney biopsy is often required to confirm the diagnosis and guide targeted treatments. However, histological findings in kidney biopsies may sometimes be nonspecific, complicating the diagnostic process. This article aims to provide an updated perspective on the role of kidney biopsy in AFD, illustrating two cases that exemplify its pivotal role in confirming or excluding the suspected disease, proving to be both decisive and confounding in this complex clinical setting.

Keywords: Anderson-Fabry Disease; Genetic test; Kidney biopsy; Zebra bodies.

Fig. 1

Light microscopy. Patient 1. Podocytes vacuolization. (a) Periodic acid–Schiff stain; (b) Hematoxylin and eosin stain

Fig. 2

Electron microscopy. a) Patient (1) Zebra bodies in a podocyte (scale bar = 5 μm); b) Patient (2) Myeloid bodies in a podocyte

Fig. 3

Negative Gb3 immunofluorescence performed on renal sample of Patient 2. (a) Negative Gb3 (red); (b) Merge of negative Gb3 (red), positive collagen (green), and nuclei (blue). 50-µm sections were prepared using a freezing sliding microtome (HM550, Thermo Scientific, Waltham, MA, USA) to evaluate Gb3 deposits. The sections were immunostained overnight with a panel of primary antibodies, including mouse monoclonal anti-Gb3 (1:1000; TCI Chemicals, Portland, Oregon, USA), rabbit pan-neuronal marker protein gene product 9.5 (1:1000; AbD Serotec, Raleigh, NC, USA) and rabbit polyclonal anti-collagen IV (1:500; Novus Biologicals, Littleton, CO, USA). After washing, secondary antibodies were applied for an additional overnight incubation. Mouse cyanine dye fluorophores 3.18 (1:800; Jackson ImmunoResearch, West Grove, PA, USA) were used as secondary antibodies. Sections were viewed and analysed under a Nikon confocal microscopy (Eclipse Ti A1)