Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

• Published in: Circulation: Cardiovascular Genetics
• Main Authors: Adalsteinsdottir, Berglind, Palsson, Runolfur, Desnick, Robert J, Gardarsdottir, Marianna, Teekakirikul, Polakit, Maron, Martin, Appelbaum, Evan, Neisius, Ulf, Maron, Barry J, Burke, Michael A, Chen, Brenden, Pagant, Silvere, Madsen, Christoffer V, Danielsen, Ragnar, Arngrimsson, Reynir, Feldt-Rasmussen, Ulla, Seidman, Jonathan G, Seidman, Christine E, Gunnarsson, Gunnar Th
• Other Authors: 1 Univ Iceland, Fac Med, Reykjavik, Iceland 2 Landspitali Natl Univ Hosp Iceland, Div Cardiol, Reykjavik, Iceland 3 Landspitali Natl Univ Hosp Iceland, Dept Genet, Reykjavik, Iceland 4 Landspitali Natl Univ Hosp Iceland, Div Nephrol, Reykjavik, Iceland 5 Landspitali Natl Univ Hosp Iceland, Dept Radiol, Reykjavik, Iceland Show the Organization-Enhanced name(s) 6 Haukeland Hosp, Dept Cardiol, Bergen, Norway Show the Organization-Enhanced name(s) 7 Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA Show the Organization-Enhanced name(s) 8 Harvard Med Sch, Dept Genet, Boston, MA USA Show the Organization-Enhanced name(s) 9 Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA 10 Tufts Med Ctr, Hypertroph Cardiomyopathy Ctr, Div Cardiol, Boston, MA USA Show the Organization-Enhanced name(s) 11 Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA Show the Organization-Enhanced name(s) 12 Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA Show the Organization-Enhanced name(s) 13 Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark Show the Organization-Enhanced name(s) 14 Univ Copenhagen, Copenhagen, Denmark Show the Organization-Enhanced name(s) 15 Howard Hughes Med Inst, Boston, MA 02115 USA 16 Akureyri Hosp, Dept Med, Akureyri, Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Lippincott Williams & Wilkins 2017
• Subjects: Efnaskiptasjúkdómar; Hjartasjúklingar; CAR12; MAB12; NEP12; DAI12; Fabry Disease; Cardiomyopathy; Hypertrophic; Iceland; Akureyri
• Online Access: http://hdl.handle.net/2336/620297; https://doi.org/10.1161/CIRCGENETICS.116.001639

To access publisher's full text version of this article click on the hyperlink below 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). 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. 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. Akureyri Hospital Research Fund Landspitali-The National University Hospital of Iceland Research Fund Howard Hughes Medical Institute National Institute of Health Novo Nordic Foundation