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Table 1 Diagnostic criteria for a definite diagnosis of FD (adopted from Smid et al. with permission [24])

From: Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document

Definite diagnosis of FD

Males

Females

GLA mutation

GLA mutation

+

+

AGAL-A deficiency of ≤5% of mean reference value in leukocytes

normal or deficient AGAL-A in leukocytes

+

+

A or B or C

A

≥1 characteristic FD sign/symptom (Fabry neuropathic pain, cornea verticillata or clustered angiokeratoma)*

B

an increase of plasma (lyso)Gb3 (within range of males with definite FD diagnosis)

C

a family member with a definite FD diagnosis carrying the same GLA mutation

Uncertain diagnosis of FD

Males/Females

All patients presenting with a non-specific FD sign (such as LVH, stroke at young age, proteinuria) who do not fulfil the criteria for a definite diagnosis of FD have a GLA GVUS. Further evaluations are needed, following diagnostic algorithms**.

Gold standard for uncertain FD diagnoses

In subjects with an uncertain FD diagnosis, a GVUS and a non-specific FD sign, the demonstration of characteristic storage in the affected organ (e.g. heart, kidney, aside from skin) by electron microscopy analysis, according to the judgment of an expert pathologist, in the absence of medication that can lead to storage, confirms FD.

  1. *Definitions:
  2. Fabry neuropathic pain meets the ‘characteristic clinical criteria’ if there is neuropathic pain in hands and/or feet, starting before age 18 years or increasing with heat, fever. Quantitative sensory testing (QST) reveals a decreased cold detection threshold and the intraepidermal nerve fiber density is increased. There is no other cause for neuropathic pain.
  3. Angiokeratoma meet the ‘characteristic clinical criteria’ if they are clustered and present in characteristic areas: bathing trunk area, lips, and umbilicus. There is no other cause for angiokeratoma.
  4. Cornea verticillata meets the ‘characteristic clinical criteria’ if there is a whorl like pattern of corneal opacities. There is no other cause (medication induced, among other: Amiodarone, Chloroquine).
  5. **For organ specific algorithms see Smid et al. [24] and Van der Tol et al. [41].
  6. GLA mutation = mutation in the α-galactosidase A gene; AGAL-A = the lysosomal hydrolase α-galactosidase A; FD = Fabry disease; Gb3 = globotriaosylceramide; LVH = left ventricular hypertrophy; GVUS = genetic variant of unknown significance.