An α-galactosidase-A assay might her out.
Men with Fabry disease are diagnosed by demonstrating decreased α-galactosidase-A activity in plasma, leukocytes or dried blood spots (DBS), which is then confirmed by GLA mutation analysis.1,2
However, α-galactosidase-A levels do not correlate with disease severity in women.3,4 40-50% of heterozygous women with a confirmed GLA-mutation have normal or only slightly decreased α-galactosidase-A activity despite having symptoms.2 In women, α-galactosidase-A deficiency occurs only in cells where X-chromosome inactivation of the non-mutated GLA gene has occurred, so levels in plasma may not reflect the enzyme deficiency within cells.4 Therefore, an α-galactosidase-A assay is not a reliable diagnostic or prognostic test for women with Fabry disease, and results should be interpreted with caution.1,3-5
GLA gene mutation analysis can confirm Fabry disease in women, whilst plasma lyso-Gb3 levels can provide both diagnostic and prognostic support.1-3,6
Elevated lyso-Gb3 levels are a hallmark of Fabry disease in both male and female patients.6,7
Plasma lyso-Gb3 and GLA sequencing should be used together to diagnose female Fabry disease patients.6
Plasma lyso-Gb3 can be used to identify Fabry disease in female patients with normal levels of α-galactosidase-A activity.2,6 A recent study of 11,984 females suspicious of Fabry disease found that the measurement of both α-galactosidase-A activity and lyso-Gb3 biomarker concentration substantially improved the diagnostic detection of Fabry disease versus measuring enzyme activity alone.8 In female Fabry disease patients, elevated lyso-Gb3 was deemed a more important indicator of disease than low α-galactosidase-A activity in cases with one abnormal biochemical value.8 Lyso-Gb3 as a biomarker can evaluate disease activity, timing of therapeutic intervention and provide supportive diagnostic information when gene sequencing results are inconclusive.2,6
Consequently, for women, first tier testing consisting of plasma lyso-Gb3 and GLA sequencing has been shown to provide accurate sensitivity and specificity.6
PROPOSED DIAGNOSTIC DECISION TREE FOR FABRY DISEASE8
Adapted from Balendran S et al. 2019.8
α-Gal A, α-galactosidase A; DBS, dried blood spot test; GL-3, globotriaosylceramide.
GLA mutation analysis should always be performed to confirm Fabry disease in women.1-3
GLA mutation analysis remains the diagnostic method of choice for heterozygous women. Genetic testing is always needed to avoid misdiagnosis of female Fabry disease patients, as lyso-Gb3 levels and α-galactosidase-A activity may lie within a normal range.1-4
In heterozygous females, bidirectional sequencing of the coding region and exon-intron boundaries in addition to thorough clinical re-evaluation and additional biochemical tests is recommended.9 The interpretation of gene alterations should be performed by an expert and genetic counselling should be offered.9 A thorough analysis of a patient’s family pedigree and medical history by a genetic counselor should also be offered, as nine out of ten patients with Fabry disease have a positive family history for the trait.9
Ensure affected relatives are diagnosed earlier by carrying out Family screening.1
Family screening and testing can identify at-risk family members before the onset of symptoms or organ damage, using the X-linked inheritance pattern of the disease to create a family pedigree.1,3 This enables affected family members to gain earlier access to treatment and genetic counselling.1,3 One study found that, on average, there are five family members diagnosed with Fabry disease for every proband (initial patient).3
The X-linked inheritance pattern of Fabry disease is used to guide family screening3
Adapted from Germain DP. 2010.1
Make sure she’s not out. Use family screening to identify hard-to-diagnose female patients.
Family screening is particularly important for female patients.3 As inheritance of Fabry disease is no longer considered recessive but X-linked, family screening is vital to identify female members not previously considered capable of having severe or treatable symptoms.3
The incidence of Fabry disease in women is now thought to be double that of men, as women can inherit Fabry disease from either parent and so are at a greater risk.10 As symptoms and biochemical test results are more variable in women, family screening can help identify female patients who may otherwise be mis- or undiagnosed.1,3,11
Female relatives of Fabry disease patients should be tested to determine their status and be monitored for the appearance of symptoms if positive.3
References
- Germain DP. Orphanet J Rare Dis 2010; 5: 30.
- Nowak A et al. Mol Genet Metab 2017; 120(1-2): 57–61.
- Laney DA et al. J Genet Couns 2013; 22(5): 555–64.
- Deegan PB et al. J Med Genet 2006; 43(4): 347–352.
- Linhorst G et al. J Am Coll Cardiol 2008; 51(21): 2082.
- Stiles A et al. Mol Genet Meta 2020; 130(3): 209–214.
- Aerts J et al. Proc Natl Acad Sci U S A. 2008; 105(8): 2812–7.
- Balendran S et al. Clin Genet 2020; 97(4): 655–660.
- Gal A et al. J Inherit Metab Dis. 2011; 34(2): 509–14.
- Laney DA and Fernhoff PM. J Genet Couns 2008; 17(1): 79–83.
- Germain DP et al. Mol Genet Metab 2019; 126(3): 224–235.
- Wanner C et al. Mol Genet Metab 2019; 126(3): 210–211.
- Barba-Romero MA and Pintos-Morell G. Int J Mol Sci 2016; 17(12): 1965.
- Lenders M et al. Orphanet J Rare Dis. 2016; 11(1): 88