Fellin R, Zuliani G, Arca M, Pintus P, Pacifico A, Montali A, Corsini A, Maioli M
Second Department of Internal Medicine, University of Ferrara, Ferrara, Italy.
Nutr Metab Cardiovasc Dis. 2003 Oct;13(5):278-86. doi: 10.1016/s0939-4753(03)80032-7.
Inherited hypercholesterolemias are common disorders characterised by elevated LDL-C levels and premature coronary heart disease. We have recently described a recessive form of hypercholesterolemia (autosomal recessive hypercholesterolemia, ARH) in which LDL catabolism is reduced because of a mutation in the gene coding for an adaptor protein that impairs LDL-receptor (LDL-R) activity in the liver. The aim of this study was to characterise in detail the phenotypes of subjects with homozygous and heterozygous ARH.
We have so far identified six Italian families with ARH and studied the clinical and biochemical characteristics of 11 homozygotes (age 13-47 years) and 12 obligate heterozygotes (age 42-83 years). The study protocol included an evaluation of the lipoprotein profile, LDL-R activity in fibroblasts, LDL binding activity, and apo E genotype; a structured questionnaire (CHD risk factors, medical history, current medications); a physical examination, resting and stress ECG, ultrasound examinations (heart, carotid arteries, Achilles tendons) and coronary angiography. The pedigrees were characterised by the absence of vertical transmission; consanguinity was documented in two families. Only the two previously described Sardinian mutations, ARH1 (c.432insA) and ARH2 (c.65G > A), were identified in the probands. All of the ARH homozygotes had large tendinous xanthomas, two had exertional angina, and four a positive stress ECG. None had experienced myocardial infarction or stroke. More than half had instrumental signs of atherosclerosis such as a positive stress ECG or positive carotid echo-doppler examination. The ARH heterozygotes were consistently normal and had a normal lipid profile.
The ARH phenotype resembles that of familial hypercholesterolemia (FH) homozygotes, but ARH may be a less serious illness. The absence of vertical transmission, and the presence of mild coronary heart disease and consanguinity, can suggest a possible diagnosis of ARH. ARH might be considered a phenocopy of FH but heterozygous subjects seem to have a consistently normal phenotype.
遗传性高胆固醇血症是常见疾病，其特征为低密度脂蛋白胆固醇（LDL-C）水平升高和早发性冠心病。我们最近描述了一种隐性高胆固醇血症（常染色体隐性高胆固醇血症，ARH），由于编码衔接蛋白的基因突变导致肝脏中LDL受体（LDL-R）活性受损，从而使LDL分解代谢降低。本研究的目的是详细描述纯合子和杂合子ARH患者的表型。
到目前为止，我们已鉴定出6个患有ARH的意大利家族，并研究了11名纯合子（年龄13 - 47岁）和12名确定的杂合子（年龄42 - 83岁）的临床和生化特征。研究方案包括评估脂蛋白谱、成纤维细胞中的LDL-R活性、LDL结合活性和载脂蛋白E基因型；一份结构化问卷（冠心病危险因素、病史、当前用药情况）；体格检查、静息和应激心电图、超声检查（心脏、颈动脉、跟腱）以及冠状动脉造影。这些家系的特征是无垂直遗传；两个家族有近亲结婚记录。仅在先证者中鉴定出两个先前描述的撒丁岛突变，即ARH1（c.432insA）和ARH2（c.65G > A）。所有ARH纯合子均有大的肌腱黄色瘤，2人有劳力性心绞痛，4人应激心电图阳性。无人发生过心肌梗死或中风。超过一半的人有动脉粥样硬化的影像学证据，如应激心电图阳性或颈动脉超声多普勒检查阳性。ARH杂合子始终正常，血脂谱也正常。
ARH的表型类似于家族性高胆固醇血症（FH）纯合子，但ARH可能病情较轻。无垂直遗传、存在轻度冠心病以及近亲结婚可提示可能诊断为ARH。ARH可能被认为是FH的拟表型，但杂合子患者似乎始终具有正常表型。
