Assessment of Peripheral Nervous System Alterations in Patients with the Fabry Related GLA-Variant p.A143T.

Tim Godel,Nicole Muschol,Moritz Kronlage,Martin Bendszus,Victor-Felix Mautner,Reinhard E Friedrich,Sabine Heiland,Thomas Duning,Sima Canaan-Kühl,Markus Glatzel,Katharina Von Cossel

doi:10.3390/diagnostics10121027

Abstract

The purpose of this study is to examine alterations of the peripheral nervous system (PNS) in oligo-symptomatic patients carrying the Fabry related GLA-gene variant p.A143T by Magnetic Resonance Neurography (MRN) and skin biopsy. This prospective study assessed dorsal root ganglia (DRG) volume L3 to S2, vascular permeability of the DRG L5, S1, and the spinal nerve L5 in five patients carrying p.A143T in comparison to patients with classical Fabry mutations and healthy controls. Moreover, skin punch biopsies above the lateral malleolus of the right foot were obtained in four patients and intraepidermal nerve fiber density (IENFD) was counted individually. Compared to controls, DRG volumes of p.A143T patients were enlarged by 30% (L3, p < 0.05), 35% (L4, p < 0.05), 29% (L5, p = 0.15), 36% (S1, p < 0.01), and 18% (S2, p < 0.05), but less pronounced compared to patients carrying a classical Fabry mutation. Compared to healthy controls, vascular permeability was decreased by 40% (L5 right), 49% (L5 left), 48% (S1 right), and 49% (S1) (p < 0.01–p < 0.001), but non-significant less than patients carrying a classical Fabry mutation. Compared to sex-matched 5% lower normative reference values per decade, IENFD was decreased in three of four patients. MRN and determination of IENFD is able to detect early alteration of the PNS segment in oligo-symptomatic patients with the disease-modifying GLA-variant p.A143T on an individual basis. This procedure might also help in further GLA-variants of uncertain significance for early identification of patients with single major organ manifestation.

Highlights

Fabry disease (FD) is a life-limiting, multi-organ lysosomal storage disorder with painful small fiber neuropathy (SFN) as one of its earliest clinical presentations [1,2]
The purpose of this study is to examine alterations of the peripheral nervous system (PNS) in oligo-symptomatic patients carrying the Fabry related galactosidase A (GLA)-gene variant p.A143T by Magnetic Resonance Neurography (MRN) and skin biopsy
By applying high-resolution peripheral nerve imaging (MR-Neurography, MRN) in patients with classical Fabry mutations, we described the fundamental role of the dorsal root ganglia (DRG) in the development of a painful SFN as an early and predominant symptom of major organ involvement [6,7]

Summary

Introduction

Fabry disease (FD) is a life-limiting, multi-organ lysosomal storage disorder with painful small fiber neuropathy (SFN) as one of its earliest clinical presentations [1,2]. By applying high-resolution peripheral nerve imaging (MR-Neurography, MRN) in patients with classical Fabry mutations, we described the fundamental role of the dorsal root ganglia (DRG) in the development of a painful SFN as an early and predominant symptom of major organ involvement [6,7]. While there is an agreement on diagnostic criteria and treatment of multi-symptomatic patients carrying a classical, disease-causing mutation in general, the therapeutic strategies in oligo-symptomatic patients with a disease-modifying variant are still under debate [10]. In a recent study in a group of oligo-symptomatic patients carrying the p.D313Y variant, we were able to show by MRN that these patients reveal pathological PNS features, which are commonly seen in multi-symptomatic Fabry patients with classical mutations [17]. To assess early PNS alterations on an individual basis, we here investigated oligo-symptomatic patients with the high-prevalent GLA-gene variant p.A143T by morphometric and functional MRN and skin biopsy

Objectives

Methods

Results

Discussion

Conclusion