Fig 1.
Flow chart of the principle of the procedure of the cascade screening.
Cascade screening begins once an index-case has been identified. Three generations surrounding the index-case are genetically screened. Each time a family member with a pathogenic GLA variant is identified, the procedure is repeated. When the index-case/family member with a pathogenic GLA variant was male, his mother, his daughter and all his siblings were offered testing. When the index-case/family member with a pathogenic GLA variant was female, both her parents, and all her children were offered testing and depending on the parents’ result, either only her female siblings in case of a father with pathogenic GLA variant or all her siblings in case of a mother with pathogenic GLA variant were tested (♂ = male, ♀ = female).
Fig 2.
Structure of human GLA and positions of the amino acid substitutions resulting from the missense pathogenic variants identified in the Danish Fabry patients.
The backbone is displayed as a ribbon model, and the ligand and sugars as a stick model. The amino acids involved in the substitutions and the catalytic residues (D170 and D231) are indicated as a space-filling calotte (Corey-Pauling-Koltun CPK) model. Front view (top) and back view (bottom).
Table 1.
The 26 families, their 115 Fabry disease patients and their corresponding GLA-gene variants of the Danish Fabry disease register.
Type of the GLA gene pathogenic variants, protein nomenclature, colloquial nomenclature, coding sequence (according to http://varnomen.hgvs.org), site of mutation and genotype classification (according to International Fabry Disease Genotype-Phenotype Database (dbFGP) http://dbfgp.org/dbFgp/fabry/ and the http://fabry-database.org) are presented. Sex, age (in years) and the primary clinical manifestation at Fabry disease diagnosis of the index-cases are presented.
Table 2.
Illustration of the affected individuals of the Danish Fabry cohort at diagnosis and/or baseline assessment from 2001 onwards and at the end of the study period.
Index patients and their family members were described in terms of age at diagnosis, sex, dead/alive at end of study, age at end of the study or age at death, no contact and first organ manifestation of the index patients.
Fig 3.
Residual α-galactosidase A activity in Fabry males and females.
Activity is expressed, as nmol/h/mg protein. Grey area represents the normal α-galactosidase A activity range (20–65 nmol/h/mg protein). Available measurements in n = 35/39 males and females n = 61/76 females. ****: p-value <0.001.