Deficient α-galactosidase-A activity that underlies Fabry disease is caused by mutations to the GLA gene, which was thought to be inherited in an X-linked recessive pattern.1,2 Because of this, heterozygous women were incorrectly described as only carriers of the defective GLA gene.2,3
Symptoms in carriers were expected to rarely develop and, if present, be very mild.4 Only hemizygous men were thought to be capable of experiencing severe symptoms.4
The mutated GLA gene was thought to be an X-linked recessive inherited trait.
Adapted from Germain DP. 2010.3
It was thought only male patients could have symptoms.
The clinical features of Fabry disease are well defined in male patients. The onset of severe and multisystemic symptoms occurs at an average age of 9 years old, with men usually displaying all of the characteristic clinical features.3-6
Clinical manifestations of classic Fabry disease6
Adapted from Ortiz A et al. 2018.
CT, computed tomography; ECG, electrocardiography; GL-3, globotriaosylceramide; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging; TIA, transient ischaemic attack; TRPV1, transient receptor potential vanilloid 1.
Women do develop symptoms, but their presentation may be different to men.1,6
Multiple studies have shown that the majority of women develop symptoms.2,5,7 Hence, the scientific community no longer considers inheritance of Fabry disease to be recessive and states the term ‘carrier’ should be avoided.2,3
The prevalence of symptoms in women with Fabry disease
Adapted from Wilcox WR et al. 2008.6
Lyonization may explain women’s varied symptom presentation.3,4
Women’s variable symptom expression may be due Lyonization, a process that causes one of the two X-chromosomes in each cell of a female embryo to be inactivated.2-4
Women may be highly symptomatic as a consequence of skewed X-chromosome inactivation, which can cause a higher percentage of the X chromosome bearing the mutated gene to be expressed.3 Heterozygous women are therefore a ‘mosaic’ of normal and mutant cells in varying proportions, with patchy and variable expression of the defective gene.2-4
It is important that the variability and delayed onset of women’s symptoms are considered when diagnosing or monitoring female patients.3,6
Women can have variable signs and symptoms of Fabry disease due to Lyonization3,4
Adapted from Taherian M et al. 2018.9
Cardiac complications are the leading cause of death in both male and female Fabry disease patients.9
Left ventricle hypertrophy (LVH) and fibrosis are the hallmarks of cardiomyopathy in Fabry disease and are particularly detrimental for cardiac health.9,10 Approximately one third of female and up to half of male patients will develop LVH-related cardiac symptoms.9
Cardiomyopathy development is sequential in male Fabry disease patients.10
In male patients, cardiomyopathy development is sequential.10 LVH starts during adolescence and is accompanied by reduced longitudinal function.10 The hypertrophy progresses quite fast and leads to replacement fibrosis – a moderate amount of LVH is needed for the development of replacement fibrosis.10
In general, the progression toward cardiomyopathy is monitored by echocardiographic assessment of end-diastolic left ventricular wall thickness (LVWT).10 By contrast, cardiac magnetic resonance (CMR) and strain rate imaging are often proposed as optional.10
Development and assessment of cardiomyopathy is different in female Fabry disease patients.10
Progression towards hypertrophy is prolonged in female patients because of residual α-galactosidase-A activity. This means women with Fabry disease can develop fibrosis and lose myocardial function without showing LVH.10 50% of female patients with cardiomyopathy would be unrecognised by current standard assessments.10 Therefore, staging and monitoring of female Fabry disease patients should routinely include the assessment of replacement fibrosis.10
CMR and late enhancement (LE) imaging are necessary to evaluate cardiomyopathy in women with Fabry disease.10
Cardiomyopathy disease progression differs between male and female Fabry disease patients10
Adapted from Niemann M, et al. 2011.10
Unrecognised symptoms in women with Fabry disease lead to delays in diagnosis.1,5
Un- or misdiagnosed women with Fabry disease are out of treatment.
If untreated, women's progressive symptoms could lead to the development of irreversible organ damage and life-threatening complications which may reduce their life expectancy by approximately 10 years.3,5,12 As recommended by a European panel of Fabry experts, early treatment initiation is needed to prevent or treat the effects of organ damage on quality of life and long-term prognosis.12,13
References
- Germain DP et al. Mol Genet Metab 2019; 126(3): 224–235.
- Deegan PB et al. J Med Genet 2006; 43(4): 347–352.
- Germain DP. Orphanet J Rare Dis 2010; 5: 30.
- Guffon N. J Med Genet 2003; 40(4): e38. doi: 10.1136/jmg.40.4.e38.
- Wilcox WR et al. Mol Genet Metab 2008; 93(2): 112–28.
- Ortiz A et al. Mol Genet Metab. 2018; 123(4): 416–427.
- Laney DA et al. J Genet Couns 2013; 22(5): 555–64.
- Taherian M et al. Int Clin Neurosci J 2016; 3(2): 81–91.
- Wanner C et al. 2018 Mol Genet Metab. 2018; 124(3): 189–203.
- Niemann M et al. JACC Cardiovasc Imaging 2011; 4(6): 592–601.
- MacDermot KD et al. J Med Genet 2001; 38(11): 769-75.
- Biegstraaten M et al. Orphanet J Rare Dis 2015; 10: 36.
- Wanner C et al. Mol Genet Metab 2019; 126(3): 210–211.