Study of gene mutations of cardiac Fabry disease

法布里病是一种X连锁隐性遗传疾病，由α-半乳糖苷酶（α-Gal）缺乏引起。我们曾报道心脏Fabry病的临床表现仅限于心脏，在男性左心室肥大（LVH）患者中的发病率约为3%。然而，心脏的调查结果和酶活性还没有研究男性患者（半合子）和女性患者（杂合子）在心脏Fabry family.Methods：为了澄清基因突变，α-半乳糖苷酶活性和心脏的调查结果，我们进行了DNA分析，并测量血浆α-半乳糖苷酶活性，并评估左室肥厚（13毫米或更大），通过超声心动图在7个心脏Fabry家族。结果：7个家系中有3个家系检测到3个点突变。这些突变是外显子1中的Ala 20 Pro、外显子2中的Glu 66 G1 n和外显子6中的Met 296 I1 e。其余4个家系在α-Gal基因编码区没有任何突变，但通过北方印迹分析，α-Gal信使RNA的量显著降低。通过DNA分析或α-Gal活性测定，在7个心脏法布里病家系中诊断出11个半合子（年龄12 - 72岁）和15个杂合子（年龄27 - 84岁）。所有半合子的α-Gal活性都很低。15个杂合子中有12个具有中等程度的低活性，但其余3个具有正常活性。这3例杂合子均为第2外显子Glu 66 Gln突变，需DNA分析确诊。除了一个12岁的半合子外，所有的半合子都有LVH。10个半合子中有3个有不对称的间隔肥大。无左心室流出道梗阻。所有15个杂合子没有LVH。结论：DNA分析是有用的检测杂合子，因为一些杂合子有正常的α-Gal活性。在心脏Fabry家族中，几乎所有的半合子都观察到LVH，但不是所有的杂合子。心脏法布里病表现为X连锁左心室肥大。

Fabry disease is an X-linked recessive disorder that results from deficiency of alpha-galactosidase (alpha-Gal). We have reported that cardiac Fabry disease had clinical manifestations limited to the heart and the incidence is about 3% among male patients with left ventricular hypertrophy (LVH). However, cardiac findings and enzyme activity have not been studied in male patients (hemizygotes) and female patients (heterozygotes) in cardiac Fabry families.Methods : To clarify gene mutations, a-Gal activity and cardiac findings, we performed DNA analysis, and measured plasam alpha-Gal activity, and assessed LVH (13mm or greater) by echocardiography in seven cardiac Fabry families. Results : Three point mutations were detected in three of the seven families. These mutations were Ala20Pro in exon 1, Glu66G1n in exon 2, and Met296I1e in exon 6. Remaining four families did not have any mutations in the coding region of the alpha-Gal gene, but markedly decreased amount of a-Gal messenger RNA by Northern blot analysis. Eleven hemizygotes (in age 12 - 72 years) and fifteen heterozygotes (in age 27 - 84 years) were diagnosed in seven cardiac Fabry families by DNA analysis or measurements of alpha-Gal activity. All hemizygotes had very low activitiy of alpha-Gal. Twelve of the 15 heterozygotes had moderately low activities, but remaining three had normal activities. These three heterozygotes with a mutation of Glu66Gln in exon 2, needed DNA analysis to make diagnosis. All hemizygotes had LVH except one, who was 12-year-old. Three of the 10 hemizygotes had asymmetrical septal hypertrophy. None had left ventricular outflow obstruction. All fifteen heterozygotes did not have LVH.Conclusions : DNA analysis was useful to detect heterozygotes, because some hetrozygotes had normal alpha-Gal activity. LVH was observed in almost all hemizygotes but not in all heterozygotes in the cardiac Fabry families. Cardiac Fabry disease shows an X-linked left ventricular hypertrophy.