Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles
© The Author(s). 2016
Received: 19 January 2016
Accepted: 15 June 2016
Published: 19 July 2016
X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown.
This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations.
This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation.
KeywordsFabry disease Cryptogenic stroke Pain Hypertrophic cardiomyopathy Chronic kidney disease
Anderson-Fabry disease (FD) is a rare, X-chromosomal inherited lysosomal storage disorder resulting from currently over 800 known pathogenic alpha-galactosidase A gene (GLA) mutations [1, 2]. Recent focus has been set on understanding mutation-specific clinical characteristics and outcome, which might eventually lead to a clinically relevant sub-classification of FD, such as into classical, non-classical, “late onset” and/or organ-specific variants [3–6]. While most X-linked diseases only cause phenotypical manifestations in male patients with females usually being completely unaffected carriers [7, 8], FD-females may develop manifestations to a specific extent, which are usually much less severe in terms of clinical symptoms compared to respective men [2, 9, 10]. This is attributed to the fact that women nearly always present a heterozygous GLA genotype including one further, non-pathologically affected allele. However, the definite underlying mechanisms ultimately leading to somewhat less morbidity in female FD patients are still under debate. A potential impact of skewed X-inactivation has been supposed central, leading to random transcriptional silencing of one of both X‐chromosomes in every cell, eventually leading to the typical findings of female genetic mosaicism [8, 11, 12]. Due to the marked variance of FD regarding clinical symptoms, there is high interest to characterize the impact of genotypes in order to embrace patients individualized additive therapeutic needs aside from enzyme replacement therapy (ERT) and improve mechanistic knowledge regarding genotype-phenotype pathophysiology.
All patients attending the Fabry Center for Interdisciplinary Therapy (FAZIT) Wurzburg, Germany, undergo a standardized comprehensive clinical, laboratory and imaging examination with special focus on Fabry-related impairments and organ involvement. Cardiac imaging modalities include standard two-dimensional echocardiography, as well as speckle tracking analysis, and cardiac magnetic resonance tomography (MRI), both beneficial for indirect quantification of intramural fibrosis as prominently seen in advanced Fabry cardiomyopathy [13–15]. Investigations also include a thorough investigation of the kidneys including biopsy if suitable, central and peripheral nervous system including brain MRI, skin biopsy, and assessment of sweating capacity, and psychic factors, including assessment of quality of life using SF-36.
In late 2015, a 45-year-old female patient with genetically proven FD approached FAZIT for specialized clinical evaluation and therapy induction. Molecular gene analysis revealed the atypical situation of a heterozygous female patient carrying two different haplotype variants – c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, one on each X-chromosomal allele – which both have previously been described as potentially pathogenic [16, 17]. Due to the low frequency of pathogenic GLA mutations in the population, comparable respective cases are extremely rare. The initial suspicion for FD in this index patient was raised during a routine ophthalmologist checkup leading to the discovery of Fabry-specific depositions in her cornea at young age of six years. Later on, it was revealed that not only her mother, but also her brother are both affected by the same mutational variant (c.708G > C, p.W236C in exon 5), which was in both relatives clinically related to Fabry-associated acral pain, myocardial hypertrophy, and renal dysfunction. In addition, the index patient’s brother suffered from young-aged stroke at age 45 years and now receives hemodialysis due to end-stage chronic kidney disease. Her grandfather from maternal site is anticipated to have been affected by FD, suffering from fatal end-stage kidney disease at his early forties. Unfortunately, the index patient’s 74 years old father refused to undergo genetic analysis. As the index patient never subjectively suffered from any health problems, neither doctors were consulted nor medication taken until the event of young-aged cryptogenic stroke at the age of 44 years. As a result of stroke, she attended FAZIT for clinical examination and initiation of life-time ERT.
General- and Fabry-associated characteristics, biomarkers, renal function and quality of life of the index patient
Age at first visit (years)
α-Gal A (nmol/min/mg protein)
Cystatin C (mg/l)
GFR DTPA Clearance (ml/min)
Quality of life (SF-36 questioner)
Physical component summary score
Mental component summary score
Cardiac features and imaging modalities results in the index patient
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Heart rate (bpm)
Cardiac stress test
maximal heart rate (bpm)
maximal watts (watts)
Speckle tracking strain [%]
Speckle tracking strain rate [S−1]
global strain rate
basal strain rate
mid strain rate
apical strain rate
septal strain rate
lateral strain rate
normalized LVM (g/m2)
normalized ESV (ml/m2)
normalized EDV (ml/m2)
normalized SV (ml/m2)
By rules of genetic penetrance, in this particular case the index patient conducts one of her pathogenic GLA alleles to all of her biological descendants. Thus both of her children, an 11 year old daughter and her 8 year old son underwent genetic analysis for FD (Centogene AG, Rostock, Germany), both presenting the c.708G > C, p.W236C mutation in exon 5. α-Gal A enzyme activity was reduced in her daughter (0.20 nmol/min/mg protein in leucocytes) and highly reduced in the index patient’s son (0.03 nmol/min/mg protein in leucocytes). Lyso-Gb3 was 8.1 ng/ml in the index patient’s daughter and not determined in her son. Interestingly, her son already claims about stinging pain occurring in situations of bodily stress and during infections even though he is at very young age.
Female mutation carriers usually present milder phenotypes than comparable males, which might be explained due to compensatory effects of the second, non-pathologically affected allele. In rare cases of homozygous female patients classical FD is to be expected. In this regard, Rodríguez-Marí and colleagues reported about a young female patient, who was found homozygous for the Q279R GLA mutation and presented a classics Fabry-phenotype with cardiac and neurological organ involvement, reduced α-Gal A activity, Fabry-associated angiokeratoma, a reduced sweating capacity and acral pain, which started at young age of 8 years . In contrast, all three female homozygous patients (p.Arg118Cys variant) published by Susana Ferreira and colleagues did not develop a classical Fabry phenotype, highlighting the impact of mutation-specific factors in FD . However, contradictory to both mentioned reports, the index patient of the current study was found homozygous with not one and the same, but two different GLA mutations in each of her alleles. Regarding our index patient, family pedigree, laboratory data, and clinical manifestations give a mixed picture regarding disease patterns. While young-aged stroke gives evidence for neurological manifestations, further organ involvement was minimal with only very mild cardiac and no renal impairments detectable. Comparing her clinical course to her brothers’, much less severe manifestations were found. This could indicate that there might not be an additive effect of two independent pathogenic GLA alleles, questioning the anticipated clinical impact of skewed X-inactivation leading to silence of the index patient’s second pathogenic allele. It might instead be speculated that there could be so far unknown additional modifying effects in females, preventing severe clinical courses including e.g. chronic renal disease. These assumptions remain limited due to the scarce comprehensive data about p.N139S available in literature, discussing this respectively novel mutation being of pathogenic impact . However, long-term results remain to be evaluated in order to judge on clinical severity and outcome over time.
Both of the index patient’s children are likely to develop organ involvement as seen in their biological relatives. As therapeutic effects of ERT have been reported to be most beneficial when started before organ injury is detectable [21, 22], it is to be discussed whether and when the index patient’s children should start receiving ERT, particularly in the light of the high prevalence of young-aged stroke in the family pedigree.
In summary, this current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional uncommon constellations and are thus in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers require further investigation.
α-Gal A, alpha-galactosidase A; ERT, enzyme replacement therapy; FAZIT, Fabry Center for Interdisciplinary Therapy Würzburg; FD, Fabry disease; GLA, alpha-galactosidase A encoding gene; LV, left ventricle of the heart.
This work was supported by the Bundesministerium für Bildung und Forschung of the Federal Republic of Germany (BMBF 01EO1504 MO2 to Peter Nordbeck and Christoph Wanner). We thank Mrs. Irina Turkin for her long-standing dedicated work at FAZIT.
Conception and design: DO, PN; analysis and interpretation of data: DO, DV, GE, CW, PN; drafting the article: DO, PN; revising the article: DO, DV, GE, CW, PN. All authors read and approved the final manuscript.
Potential conflicts of interest: DO received travel assistance from Genzyme Corporation, Cambridge, Massachusetts, and Shire Plc., Dublin, Ireland. DV received travel assistance from Genzyme Corporation, Cambridge, Massachusetts, and Shire Plc., Dublin, Ireland. GE reports no competing interest. CW received travel assistance, speaker’s/advisory board honoraria, and research support from Genzyme and Shire. PN received travel assistance, speaker’s/advisory board honoraria, and research support from Genzyme and Shire.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available.
Ethics approval and consent to participate
The investigations were approved by the local ethics committee of the University Hospital Würzburg, Bavaria, Germany.
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- Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338–46.View ArticlePubMedGoogle Scholar
- Froissart R, Guffon N, Vanier MT, Desnick RJ, Maire I. Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. Mol Genet Metab. 2003;80(3):307–14.View ArticlePubMedGoogle Scholar
- Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.View ArticlePubMedPubMed CentralGoogle Scholar
- Lin HY, Chong KW, Hsu JH, Yu HC, Shih CC, Huang CH, Lin SJ, Chen CH, Chiang CC, Ho HJ, et al. High incidence of the cardiac variant of Fabry disease revealed by newborn screening in the Taiwan Chinese population. Circ Cardiovasc Genet. 2009;2(5):450–6.View ArticlePubMedGoogle Scholar
- van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet. 2014;51(1):1–9.View ArticlePubMedGoogle Scholar
- Morey C, Avner P. Genetics and epigenetics of the X chromosome. Ann N Y Acad Sci. 2010;1214:E18–33.View ArticlePubMedGoogle Scholar
- Elstein D, Schachamorov E, Beeri R, Altarescu G. X-inactivation in Fabry disease. Gene. 2012;505(2):266–8.View ArticlePubMedGoogle Scholar
- MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38(11):769–75.View ArticlePubMedPubMed CentralGoogle Scholar
- MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750–60.View ArticlePubMedPubMed CentralGoogle Scholar
- Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC, Elleder M, Karetova D, Pavlikova M, Hrebicek M. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med. 2005;83(8):647–54.View ArticlePubMedGoogle Scholar
- Maier EM, Osterrieder S, Whybra C, Ries M, Gal A, Beck M, Roscher AA, Muntau AC. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr. 2006;95(451):30–8.View ArticleGoogle Scholar
- Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J cardiovasc Imaging. 2015;16(3):233–70.View ArticlePubMedGoogle Scholar
- Kramer J, Niemann M, Liu D, Hu K, Machann W, Beer M, Wanner C, Ertl G, Weidemann F. Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease. Eur Heart J. 2013;34(21):1587–96.View ArticlePubMedGoogle Scholar
- Weidemann F, Ertl G, Wanner C, Kramer J. The Fabry cardiomyopathy - diagnostic approach and current treatment. Curr Pharm Des. 2015;21(4):473–8.View ArticlePubMedGoogle Scholar
- Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot K, Winchester B, Desnick RJ. Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. Eur J Hum Genet. 1996;4(4):219–24.PubMedGoogle Scholar
- Havndrup O, Christiansen M, Stoevring B, Jensen M, Hoffman-Bang J, Andersen PS, Hasholt L, Norremolle A, Feldt-Rasmussen U, Kober L et al. Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women. Eur J Heart Fail. 2010;12(6):535–40.View ArticlePubMedGoogle Scholar
- Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M, Mehta A, Elliott PM, European FOSI. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007;28(10):1228–35.View ArticlePubMedGoogle Scholar
- Rodriguez-Mari A, Coll MJ, Chabas A. Molecular analysis in Fabry disease in Spain: fifteen novel GLA mutations and identification of a homozygous female. Hum Mutat. 2003;22(3):258.View ArticlePubMedGoogle Scholar
- Ferreira S, Ortiz A, Germain DP, Viana-Baptista M, Caldeira-Gomes A, Camprecios M, Fenollar-Cortes M, Gallegos-Villalobos A, Garcia D, Garcia-Robles JA, et al. The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies. Mol Genet Metab. 2015;114(2):248–58.View ArticlePubMedGoogle Scholar
- Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015;52(5):353–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Stork S, Voelker W, Ertl G, Wanner C, Strotmann J. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119(4):524–9.View ArticlePubMedGoogle Scholar