肥厚型心肌病家族中的法布里病：经典型和迟发型表型的临床表现

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

作者信息

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

机构信息

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.).

出版信息

Circ Cardiovasc Genet. 2017 Aug;10(4). doi: 10.1161/CIRCGENETICS.116.001639.

DOI:10.1161/CIRCGENETICS.116.001639

PMID:28798024

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 (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 missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

摘要

背景

对临床诊断为肥厚型心肌病的冰岛患者进行筛查，结果从2个家族中鉴定出8名患有X连锁法布里病（FD）的个体，这些患者由编码p.D322E（A家族）或p.I232T（B家族）的（α - 半乳糖苷酶A基因）突变引起。

方法与结果

对有风险的亲属进行家族筛查，在16名A家族成员（8名男性和8名杂合子）和25名B家族成员（10名男性和15名杂合子）中发现了突变。通过临床评估、α - 半乳糖苷酶A（α - GalA）活性、糖鞘脂底物水平以及体外突变表达，将p.D322E归类为经典FD突变，p.I232T归类为迟发性FD突变。体外表达显示，p.D322E和p.I232T的α - GalA活性分别为野生型平均活性的1.4%和14.9%。A家族男性的α - GalA活性显著降低，且有儿童期起病的经典表现，但无血管角质瘤和涡状角膜病变。B家族男性有残余的α - GalA活性，并在成年期出现FD表现。尽管存在这些差异，但所有年龄大于30岁的A家族和B家族男性均有左心室肥厚，主要为不对称性，且晚期钆增强模式相似。缺血性卒中和严重白质病变在A家族男性中更为常见，但A家族和B家族男性均无明显肾病。A家族和B家族杂合子的临床表现较轻或无临床表现。