Berglind Adalsteinsdottir1, Runolfur Palsson2, Robert J Desnick2, Marianna Gardarsdottir2, Polakit Teekakirikul2, Martin Maron2, Evan Appelbaum2, Ulf Neisius2, Barry J Maron2, Michael A Burke2, Brenden Chen2, Silvere Pagant2, Christoffer V Madsen2, Ragnar Danielsen2, Reynir Arngrimsson2, Ulla Feldt-Rasmussen2, Jonathan G Seidman2, Christine E Seidman2, Gunnar Th Gunnarsson2. 1. From the Faculty of Medicine, University of Iceland, Reykjavik, Iceland (B.A., R.P., R.A., G.T.G.); Division of Cardiology (B.A., R.D.), Department of Genetics (R.A.), Division of Nephrology (R.P.), and Department of Radiology (M.G.), Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Department of Cardiology, Haukeland University Hospital, Bergen, Norway (B.A.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.J.D., B.C., S.P.); Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., J.G.S., C.E.S.); Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.A., U.N.); Division of Cardiology, Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (M.M., B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (M.A.B.); Department of Medical Endocrinology, Rigshospitalet and University of Copenhagen, Denmark (C.V.M., U.F.-R.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Department of Medicine, Akureyri Hospital, Iceland (G.T.G.). berglind.ba@gmail.com. 2. From the Faculty of Medicine, University of Iceland, Reykjavik, Iceland (B.A., R.P., R.A., G.T.G.); Division of Cardiology (B.A., R.D.), Department of Genetics (R.A.), Division of Nephrology (R.P.), and Department of Radiology (M.G.), Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Department of Cardiology, Haukeland University Hospital, Bergen, Norway (B.A.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.J.D., B.C., S.P.); Department of Genetics, Harvard Medical School, Boston, MA (P.T., M.A.B., J.G.S., C.E.S.); Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.A., U.N.); Division of Cardiology, Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (M.M., B.J.M.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.B., C.E.S.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (M.A.B.); Department of Medical Endocrinology, Rigshospitalet and University of Copenhagen, Denmark (C.V.M., U.F.-R.); Howard Hughes Medical Institute, Boston, MA (C.E.S.); and Department of Medicine, Akureyri Hospital, Iceland (G.T.G.).
Abstract
BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS: Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.
BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS:Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.
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