Study of gene mutations of cardiac Fabry disease

法布里病是一种由α -半乳糖苷酶（α -gal）缺乏引起的x连锁隐性疾病。我们曾报道心脏法布里病的临床表现局限于心脏，在左心室肥厚（LVH）的男性患者中发病率约为3%。然而，心脏法布里家族的男性患者（半合子）和女性患者（杂合子）的心脏检查结果和酶活性尚未研究。方法：为了明确基因突变、α - gal活性和心脏表现，我们进行了DNA分析，测量了血浆α - gal活性，并通过超声心动图评估了7个心脏法布里家族的LVH （13mm或更大）。结果：7个家族中有3个检测到3个点突变。这些突变是外显子1的Ala20Pro，外显子2的Glu66G1n和外显子6的Met296I1e。其余4个家族α - gal基因编码区未发生突变，但α - gal信使RNA的数量明显减少。通过DNA分析或α - gal活性测量，在7个心脏Fabry家族中诊断出11个半合子（年龄在12 - 72岁）和15个杂合子（年龄在27 - 84岁）。所有半合子α - gal活性都很低。15个杂合子中有12个活性较低，其余3个活性正常。这三个杂合子在2号外显子Glu66Gln突变，需要DNA分析才能诊断。所有的半合子都有LVH，除了一个12岁的孩子。10个半合子中有3个有不对称的间隔肥大。无左心室流出梗阻。所有15个杂合子均无LVH。结论：DNA分析对检测杂合子是有用的，因为一些杂合子具有正常的α - gal活性。在心脏法布里家族中，几乎所有半合子都有LVH，但并非所有杂合子都有LVH。心脏法布里病显示x连锁左心室肥厚。

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.