Why perform family screening?

Following a diagnosis of Fabry disease, it is recommended that a thorough pedigree analysis is performed for each patient to identify any family members at risk of Fabry disease.1,2 Family screening for Fabry disease should be conducted by healthcare professionals experienced in genetic counselling.3 Pedigree analysis can be conducted within primary care or at a specialised centre for lysosomal storage disorders. Many patients with Fabry disease experience a delay in diagnosis following the onset of symptoms; therefore, one of the advantages of family screening is the identification of family members early in the disease course. Consequently, family screening can reduce the time to diagnosis from symptom onset, eliminate misdiagnoses and enable provision of early treatment, if necessary.4 Family screening for Fabry disease may also identify patients who are at risk of having children with the disease (see prenatal and newborn screening).5

After a patient has been diagnosed with Fabry disease, a complete pedigree analysis, which includes ≥3 generations, is recommended.6 In males, the alpha-galactosidase A (α-Gal A) enzyme assay, in addition to genetic testing, can be used to confirm a diagnosis of Fabry disease.7-10 This enzyme assay is considered less reliable for diagnosing Fabry disease in females, because many female patients exhibit α-Gal A enzyme activity levels within the normal range.7,8,11 Genetic testing is therefore used to confirm a diagnosis of Fabry disease in female patients.8-10 Family members who are subsequently diagnosed with Fabry disease should also receive support and counselling.3,6

Clinical experience in family screening of Fabry disease
The results of a targeted genetic strategy for pedigree analysis of Fabry disease in Argentina were published by Rozenfeld et al. (Mol Genet Metab 2019). The aim of this targeted genetic strategy was to offer assistance to physicians who have recently diagnosed a patient with Fabry disease, referred to as the ‘index’ patient. Following diagnosis of Fabry disease in the index patient, a meeting was arranged with the patient, their family, the diagnosing physician, a biochemist, a geneticist and a social worker. During this meeting, the index patient and their family were requested to provide detailed family information and to build a family tree.12

Following genetic analysis of the index patient with Fabry disease, it was determined whether variants in the GLA gene were inherited from the parents. If the GLA gene variant was also present in the parents, the family tree was further analysed. Whilst the pedigree analysis was being completed, the biochemist and geneticist helped the diagnosing physician identify which family members could also be affected by Fabry disease. Screening for Fabry disease was performed using a step-by-step approach, beginning with the oldest family members and following the family tree of any positive relatives who were also identified. In some cases, family members did not live in the same geographic location as the index patient; investigations into these relatives were performed by the social worker. Blood samples were taken from family members who were identified as at risk for Fabry disease. In males, analysis of α-Gal A enzyme activity was determined using dried blood spots and confirmed using genetic testing. In females, a diagnosis of Fabry disease was confirmed by genetic testing.12

Between April 2003 and November 2018, using the targeted genetic strategy outlined above, a full pedigree analysis was conducted for 31 families where the GLA gene variant in the index patient was considered to be inherited. Family screening for Fabry disease in 1462 relatives led to an additional 501 relatives being diagnosed with Fabry disease. In this study, for every individual index patient diagnosed with Fabry disease, approximately 15 more cases of the disease were identified. These findings suggest that using a targeted genetic strategy to detect undiagnosed Fabry disease is important, and may lead to identification of new patients and earlier diagnosis before the onset of symptoms.12

C-ANPROM/INT/FAB/0016; Date of preparation: March 2021