Study of gene mutations of cardiac Fabry disease

法布里病是一种X连锁隐性遗传病，由α-半乳糖苷酶(α-Gal)缺乏引起。我们曾报道心脏Fabry病的临床表现局限于心脏，在男性左心室肥厚(LVH)患者中的发生率约为3%。然而，在心脏Fabry家族中，男性患者(半合子)和女性患者(杂合子)的心脏表现和酶活性尚未被研究。方法：对7个心脏Fabry家族进行DNA分析，测定血浆α-Gal活性，并通过超声心动图评估左心室肥厚(13 mm或以上)，以明确基因突变、α-Gal活性和心脏发现。结果：在7个家系中有3个家系检测到3个点突变。这些突变分别是外显子1的Ala20Pro、外显子2的Glu66G1n和外显子6的Met296I1e。其余4个家系的α-Gal基因编码区没有任何突变，但Northern印迹分析显示α-Gal信使RNA的含量显著减少。通过DNA分析或α-Gal活性测定，在7个心脏Fabry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-半乳糖活性都很低。在15个杂合子中，有12个具有中等低活性，但其余3个具有正常活动。这三个外显子2 Glu66Gln突变的杂合子需要DNA分析才能做出诊断。所有的半合子都有左心室肥厚，除了一名12岁的男孩。10个半合子中有3个有不对称性室间隔肥厚。无左室流出道梗阻。结论：DNA分析有助于杂合子的检测，因为部分杂合子具有正常的α-Gal活性。在心脏Fabry家族中，几乎所有的半合子都观察到了LVH，但并不是所有的杂合子都观察到了LVH。心脏法布里病表现为X连锁的左心室肥厚。

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.