Data dictionary

Phenotype

For all patients in the database, their phenotype was defined using the criteria stated below. In case of remaining uncertainty or debate, the final judgement on the phenotype was made by the treating physician. For this decision, clinical, histopathological and biochemical characteristics (as described in the flow chart) were used.

Classical

Patients with classical FD usually present with characteristic FD symptoms (neuropathic pain, angiokeratoma and/or cornea verticillata)(for definition of these symptoms see table*. Long term disease manifestations include hypertrophic cardiomyopathy, cardiac rhythm disturbances, progressive renal failure and stroke.

Classical FD in men is defined as a patient with all three of the following:

  • a variant in the GLA gene
  • enzyme activity ≤ 5% of the mean of the reference range
  • ≥1 characteristic Fabry symptom(s)

In women classical Fabry disease is defined as a patient with both:

  • a variant in the GLA gene
  • ≥1 characteristic Fabry symptom(s)

The following criteria can additionally support the diagnosis classical FD:

  • a lysoGb3 level >50 nmol/L (usually in males)
  • a family member with an established diagnosis of classic FD using the above stated criteria.

*Definition of characteristic FD symptoms (van der Tol et al 2014)

Symptom

Definition

Neuropathic pain

Neuropathic pain related to small fibre neuropathy in hands and/or feet, starting before age 18 or increasing with heat, fever. Quantitative sensory testing (QST) reveals a decreased cold detection threshold and the intraepidermal nerve fibre density (IENFD) is decreased. There is no other cause for Fabry neuropathic pain.

Angiokeratoma  

Angiokeratoma clustered and present in characteristic areas: bathing trunk area, lips and umbilicus. There is no other cause for angiokeratoma.

Cornea Verticillata

A whorl-like pattern of corneal opacities. There is no other cause (medication induced, among others, amiodarone, chloroquine)

 

Non-classical

Non-classical FD, also referred to as late-onset or atypical FD, is characterized by a more variable disease course compared to classical FD, in which patients are generally less severely affected and disease manifestations may be limited to a single organ.

Non-classical FD is defined as a patient (male or female) with:

  • a variant in the GLA gene not previously established as a neutral variant* and whose phenotype does not fullfill the above stated criteria for a classic phenotype
  • FD related organ involvement confirmed by histopathological (EM) examination

Criteria that support or exclude a diagnosis of non-classical FD in cases in which histopathological examination has not been performed/is not possible are depicted in the flow-chart.

Benign

A benign variant in the GLA gene is a variant that is not associated with a Fabry phenotype. FD can be excluded in patients:

  • who do not fullfill criteria for a classical phenotype
  • in whom histopathological examination by electron microscopy, of an organ with dysfunction suspected to be Fabry related, demonstrated no pathological lysosomal inclusions (zebra bodies)
  • with a variant in the GLA gene that has previously been established as a neutral variant*

*Several GLA variants have previously been established as neutral variants based on:

  • pathology studies confirming the absence of characteristic storage in relevant organs in individuals with the variant
  • the high frequency of the variant in the general population
  • >50% residual enzyme activity in individuals with the variant
  • lysoGb3 concentrations <0,7 nmol/L in individuals with the variant

Variant

References

D313Y

Niemann et al JIMD reports 2013
Froissart et al MGM 2003
Yasuda et al 2003

A143T

Smid et al Clin Gen 2015
Terryn et al JIMD reports 2013

P60L

Smid et al Clin Gen 2015

R118C

Ferreira et al MGM 2015

T385A
IVS0-10C>T
IVS0-10C>T/IVS4-16A>G/IVS6-22C>T

Arends et al 2017

 

Number of patients

Number of patients in the given category. Patients are clustered into categories based on variant, sex and phenotype.

Sex

Sex of the patients in the given category

Enzyme activity (%)

Absolute values for enzyme activity vary widely based on the methods used. Therefore, enzyme activity is expressed as a percentage of the mean of the lower and upper reference value reported by the laboratory in which it was measured. Only values for enzyme activity as measured in leucocytes (as opposed to plasma) are reported. Values reported represent the median and range for patients in whom enzyme activity was assessed.
Since enzyme activity is calculated as a percentage of the mean of the lower and upper reference value, this value may exceed 100% in patients with a measured enzyme activity that is relatively high within the reference range.

Enzyme activity number

Number of patients in the given category in whom enzyme activity was measured. Patients are clustered into categories based on variant, sex and phenotype.

LysoGb3 (nmol/L)

Pre-treatment plasma lysoGb3 level as measured with an adjusted method based on tandem mass spectrometry with glycine labeled (all samples from the Royal Free Hospital and the University Hospital Wuerzburg as well as all samples from August 2015 onward from Amsterdam UMC, location AMC) or isotope labeled (samples from before August 2015 from Amsterdam UMC, location AMC) lysoGb3 as an internal standard. Results from both internal standard correlated very well. LysoGb3 has not been measured for patients in the CFDI.

LysoGb3 number

Number of patients in the given category in whom LysoGb3 level was measured. Patients are clustered into categories based on variant, sex and phenotype.

AA variant

Variant at protein level. E.g. p.Ala309Pro means that the amino acid alanine at position 309 of the GBA protein is changed into the aminoacid proline.

http://varnomen.hgvs.org/

AA variant short

Variant at the protein level, but using the one letter code instead of the three letter code. E.g. the p.Ala309Pro variant would be depicted as the A309P variant (A=alanine, P=proline)

http://varnomen.hgvs.org/

DNA variant

Variant at the cDNA level. cDNA is complementary DNA or DNA synthesized from messenger RNA. E.g. the c.925G>C variant indicates that base number 925 of the cDNA has been changed from a Guanine (G) to a Cytosine (C).

http://varnomen.hgvs.org/