NEUROLOGY/2014/599217
Thromboembolic Events in Fabry Disease and the Impact of Factor V Leiden
Malte Lenders,* PhD; Nesrin Karabul,* MD; Thomas Duning, MD; Boris Schmitz, PhD; Michael Schelleckes, MSc; Rolf Mesters, MD; Hans-Werner Hense, MD; Michael Beck, MD; Stefan-Martin Brand, MD, PhD; Eva Brand, MD, PhD
From the Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (M.L., M.S., E.B.), Department of Neurology (T.D.), Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S-M.B.), Internal Medicine A, Department of Hematology and Oncology (R.M.), Institute of Epidemiology and Social Medicine (H-W.H.), University Hospital Muenster, Germany and the Department of Pediatric and Adolescent Medicine, Villa Metabolica, (N.K., M.B.), University Medical Center of the Johannes Gutenberg University, University of Mainz, Germany.
*These authors contributed equally to the manuscript.
Supplemental Data
Missense and nonsense mutations
Amino acid / cDNA / Clinical phenotype / Reference No. / Accession number
p.L14P / c.41T>C / mild (female) / 1 / CM031693
p.A20P / c.58G>C / mild (female) / 2 / CM950584
p.G35E / c.104G>A / classic / own data
p.L45P / c.134T>C / classic / own data
p.H46R / c.137A>G / classic / 3 / CM972764
p.R49C / c.145C>T / classic / 4 / CM088111
p.C52S / c.155G>C / classic / 5 / CM940843
p.C63Y / c.188G>A / classic / 6 / CM051519
p.E66K / c.196G>A / reduced activity / 6 / CM051520
p.I91T / c.272T>C / classic / 3 / CM972767
p.C94S / c.280T>A / classic / 7 / CM012955
p.R112C / c.334C>T / classic / 8 / CM920311
p.R112H / c.335G>A / classic / 5 / CM940850
p.F113L / c.339T>A / classic / 3 / CM972770
p.R118C / c.352C>T / classic / 9 / CM061789
p.A121T / c.361G>A / mild (female) / own data
p.L129P / c.386C>T / classic / 10 / CM013727
p.L131P / c.392T>C / classic / 5 / CM940851
p.A143T / c.427G>A / classic / 3 / CM972773
p.G147R / c.440G>A / classic / 6 / CM051523
p.Y151X / c.453C>A / classic / 11 / CM051066
p.A156D / c.467C>A / classic (female) / own data
p.Q157X / c.469C>T / classic / 5 / CM940856
p.W162G / c.484T>G / classic / own data
p.W162X / c.485G>A / classic / 12 / CM993451
p.W162C / c.486G>T / classic / 13 / CM960766
p.V164G / c.491T>G / classic / own data
p.L167Q / c.500T>A / classic / own data
p.D170N / c.508G>A / classic / own data
p.C172G / c.514T>G / classic / 14 / CM033384
p.Y173X / C.519C>G / classic / 15 / CM066859
p.G183S / c.547G>A / classic / 16 / CM023791
p.M187V / c.559A>G / classic / 17 / CM003747
p.M187R / c.560T>G / classic / own data
p.W204X / c.611G>A / classic / 17 / CM003748
p.K213M / c.638A>T / classic / own data
p.N215S / c.644A>G / mild / 18 / CM930327
p.R220X / c.658C>T / classic / 19 / CM940860
p.R227X / c.679C>t / classic / 18 / CM930329
p.R227Q / c.680G>A / classic / 20 / CM930328
p.D231N / c.691G>A / classic / 21 / CM960768
p.W236C / c.708G>C / classic / 22 / CM960769
p.R252T / c.755G>C / classic / own data
p.W262X / c.785G>A / classic / 15 / CM066863
p.W262C / c.786G>C / classic / 6 / CM051527
p.P265L / c.794C>T / classic / 6 / CM051528
p.M267T / c.800 T>C / classic / own data
p.L268S / c.803T>C / classic / 6 / CM051529
p.A288D / c.863C>A / classic / 5 / CM940865
p.L294S / c.881T>C / classic / own data
p.L300P / c.899T>C / classic / 23 / CM088110
p.R301X / c.901C>T / classic / 5 / CM940866
p.R301P / c.902G>C / classic / 24 / CM012377
p.R301Q / c.902G>A / classic / 25 / CM900111
p.V316G / c.947T>G / classic / 26 / CM940867
p.D313Y / c.937G>T / WML only / 20 / CM930335
p.V316G / c.947T>G / classic / 26 / CM940867
p.I319T / c.956T>C / classic / 27 / CM101631
p.N320I / c.959A>T / classic / 6 / CM051534
p.Q321X / c.961C>T / classic / 6 / CM051535
p.G325S / c.973G>A / classic / 6 / CM051536
p.Q327X / c.979C>T / classic / own data
p.W340S / c.1019G>C / classic / own data
p.W340X / c.1020G>A / classic / 20 / CM930338
p.R342X / c.1024C>T / classic / 18 / CM930339
p.R342Q / c.1025G>A / classic / 28 / CM940868
p.L344P / c.1031T>C / classic / 6 / CM051539
p.A350P / c.1050G>C / classic / 6 / CM051541
p.Q357X / c.1069C>T / classic / 29 / HM971748
p.W399X / c.1196G>A / classic / 3 / CM972782
Insertions and deletions
cDNA / Clinical phenotype / Reference / Accession number
c.35_58 del24bp / classic / 10 / CG015547
c.42_48 del 7bp / classic / own data
c.270delC / classic / 6 / CD051753
c.413insG / classic / 6 / CI051799
c.560delT / mild (female) / own data
c.702_709 del8bp / classic / own data
c.718_719delAA / classic / 26 / CM941686
c.744_745delTA / classic / 6 / CD051754
c.762ins282bp / classic / own data
c.776delC / classic / own data
c.912del C / classic / own data
c.924delA / classic / own data
c.945del21 / classic / own data
c.1149_50insA; c.1152delG / classic / 16 / CM023807
c.1195_1196delTG / classic / own data
c.1223delA / classic / own data
c.1224dupT / classic / own data
g.100662387_100662965del / classic / 30
Exon 2_del / mild (female) / own data
Duplication Exon 2 g.2916/g.6359 / classic / own data
Intronic/splice mutations
Relative position / Clinical phenotype / Reference / Accession number
IVS0 -10C>T / neurological / 31
IVS2 ds +1 G>A / classic / 17 / CS003782
IVS2 ds +1 G>T / classic / own data
IVS2 as -2 A>G / mild / 6 / CS051685
IVS5 ds +3 A>T / classic / own data
IVS6 as -1 G>A / classic / 32 / CS971754
Supplemental references:
1. Tse KC, Chan KW, Tin VP, et al. Clinical features and genetic analysis of a Chinese kindred with Fabry's disease.Nephrol Dial Transplant 2003;18:182-186.
2. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy.N Engl J Med 1995;333:288-293.
3.Eng CM, Ashley GA, Burgert TS, et al. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. Mol Med 1997;3:174-182.
4.Shin SH, Kluepfel-Stahl S, Cooney AM, et al. Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone.Pharmacogenet Genomics 2008;18:773-780.
5.Eng CM, Niehaus DJ, Enriquez AL, et al. Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identiification of a deletional hot-spot in the alpha-galactosidase A gene. Hum Mol Genet 1994;3:1795-1799.
6.Schäfer E, Baron K, Widmer U, et al. Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.Hum Mutat 2005;25:412.
7.Blaydon D, Hill J, Winchester B.Fabry disease: 20 novel GLA mutations in 35 families. Hum Mutat 2001;18:459.
8.Ishii S, Sakuraba H, Suzuki Y.Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum Genet 1992;89:29-32.
9.Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset fabry disease revealed by newborn screening.Am J Hum Genet 200;79:31-40.
10.Whybra C, Kampmann C, Willers I, et al. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 2001;24:715-24.
11.Shabbeer J, Robinson M, Desnick RJ. Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography. Hum Mutat 2005;25:299-305.
12.Rosenberg KM, Schiffmann R, Kaneski C, et al. Five novel mutations in fourteen patients with Fabry Disease. Hum Mutat 2000;15:207-208.
13.Germain D, Biasotto M, Tosi M, et al. Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum Genet 1996;98:719-726.
14.Yasuda M, Shabbeer J, Benson SD, et al. Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele. Hum Mutat 2003;22:486-492.
15.Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2006;2:297-309.
16.Shabbeer J, Yasuda M, Luca E, Desnick RJ. Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. Mol Genet Metab 2002;76:23-30.
17.Ashton-Prolla P, Tong B, Shabbeer J, et al. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Investig Med 2000;48:227-235.
18.Davies JP, Winchester BG, Malcolm S. Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum Mol Genet 1993;2:1051-1053.
19.Meaney C, Blanch LC, Morris CP. A nonsense mutation (R220X) in the alpha-galactosidase A gene detected in a female carrier of Fabry disease. Hum Mol Genet 1994;3:1019-20.
20.Eng CM, Resnick-Silverman LA, Niehaus DJ, et al. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet 1993;53:1186-1197.
21.Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, et al. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet 1996;33:682-688.
22.Davies JP, Eng CM, Hill JA, et al. Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries. Eur J Hum Genet 1996;4:219-224.
23.Shin SH, Kluepfel-Stahl S, Cooney AM, et al. Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone. Pharmacogenet Genomics 2008;18:773-780.
24.Ashley GA, Shabbeer J, Yasuda M, Eng CM, Desnick RJ. Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype. J Hum Genet 2001;46:192-196.
25.Sakuraba H, Oshima A, Fukuhara Y, et al. Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet 1990;47:784-789.
26.Davies J, Christomanou H, Winchester B, Malcolm S. Detection of 8 new mutations in the alpha-galactosidase A gene in Fabry disease. Hum Mol Genet 1994;3:667-669.
27.Sirrs S, Clarke JT, Bichet DG, et al. Baseline characteristics of patients enrolled in the Canadian Fabry Disease Initiative. Mol Genet Metab 2010;99:367-373.
28.Ploos van Amstel JK, Jansen RP, de Jong JG, Hamel BC, Wevers RA. Six novel mutations in the alpha-galactosidase A gene in families with Fabry disease. Hum Mol Genet 1994;3:503-505.
29.Utsumi K, Yamamoto N, Kase R, et al. High incidence of thrombosis in Fabry's disease. Intern Med 1997;36:327-329.
30.Marziliano N, Sapere N, Orsini F, et al. A quantitative-PCR protocol rapidly detects αGAL deletions/duplications in patients with Anderson-Fabry disease. Mol Genet Metab 2012;105:687-689.
31.Oliveira JP, Ferreira S, Reguenga C, Carvalho F, Månsson JE. The g.1170C>T polymorphism of the 5' untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression--evidence from a family study. J Inherit Metab Dis 200;31:405-413.
32.Matsumura T, Osaka H, Sugiyama N, et al. Novel acceptor splice site mutation in the invariant AG of intron 6 of alpha-galactosidase A gene, causing Fabry disease. Mutations in brief no. 146. Online. Hum Mutat 1998;11:483