Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

Abstract

Introduction: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the a-galactosidase A (GLA) gene may be unclear. This uncertainty often leads to considerable distress and inappropriate counselling and treatment. We developed a clinical approach for these individuals with an uncertain diagnosis of FD.Materials and Methods: A document was presented to an FD expert panel with background information based on

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease

“…Third, we did not systematically conduct renal biopsies in our patients, also LysoGb3 measurements over time were not available in this “old” FD population. However, follow-up kidney biopsies and LysoGb3 in FD patients could assess treatment response, exclude renal pathologies beyond Fabry nephropathy and confirm diagnosis in uncertain cases [47-49]. Fourth, mathematical disease progression modeling should ideally contain histological findings based on scoring system for renal pathology in Fabry nephropathy [50].…”

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

“…Patients were classified as classical or nonclassical FD on the basis of their enzyme activity (men only) and the presence or absence of characteristic symptoms (Table 3). 39 Men were considered to have a classical phenotype when they met the following criteria: (1) a GLA mutation, (2) enzyme activity #5% of the mean reference range, and (3) one or more characteristic FD symptoms (i.e., Fabry neuropathic pain, angiokeratoma, and/or cornea verticillata; definitions are in van der Tol et al 40 ). Men not fulfilling these criteria were categorized as nonclassical FD.…”

Cornea verticillata supports a diagnosis of Fabry disease in non-classical phenotypes: results from the Dutch cohort and a systematic review

“…The whorl-like pattern of corneal opacities is specific for FD,5 with the exception of some medications that may induce a corneal whorling that cannot be distinguished from that in FD (among others, amiodarone and chloroquine; for review, see Hollander and Aldave6). With this study we aim to value the presence of CV in the diagnosis of FD by investigating the prevalence of CV in individuals with a classical or non-classical FD phenotype and in individuals with an uncertain diagnosis of FD or no FD.…”