Booth D R, Tan S Y, Hawkins P N, Pepys M B, Frustaci A
Immunological Medicine Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Circulation. 1995 Feb 15;91(4):962-7. doi: 10.1161/01.cir.91.4.962.
Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance.
Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported.
We have identified a novel mutation in the transthyretin gene encoding 59Thr-->Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.
淀粉样变性是一种蛋白质代谢紊乱疾病，其特征为细胞外异常蛋白原纤维的积累。在不同形式的疾病中，不同的蛋白质形成原纤维，该病症可以是获得性的或遗传性的。心脏受累相当常见，会导致严重且通常致命的心肌病。心脏淀粉样变性常常诊断较晚，心脏活检以及适当的组织学检查至关重要。与先前的认知相反，最近有许多证据表明，针对几种不同类型的系统性和心脏淀粉样变性，包括由转甲状腺素蛋白基因突变引起的最常见遗传性形式，存在有效的治疗方法。因此，淀粉样蛋白的化学和基因分型具有相当重要的临床意义。
一个意大利家族的两代人中的七名成员患有作为常染色体显性遗传的心脏病，并被发现患有系统性淀粉样变性。心绞痛样疼痛是心脏淀粉样变性中不常见的特征，却是一个突出症状，可能与淀粉样蛋白浸润导致远端冠状动脉部分闭塞有关。也有心脏性猝死病例。遗传性淀粉样变性的常见特征——周围神经病变和自主神经病变仅在两例中出现，在家族病史出现之前，索引病例被怀疑为获得性免疫球蛋白轻链（AL型）淀粉样变性。事实上，淀粉样原纤维由转甲状腺素蛋白组成，可获取DNA的两名受影响个体均为转甲状腺素蛋白基因第3外显子单个碱基变化的杂合子，该变化编码成熟蛋白中第59位野生型苏氨酸残基被赖氨酸替代。此突变此前未见报道。
我们在一个以心脏受累为主要特征的意大利家族中，发现了转甲状腺素蛋白基因编码59Thr→Lys的一种新突变，该突变与常染色体显性遗传的系统性淀粉样变性相关。这个家族说明了心脏淀粉样变性诊断的困难、遗传性淀粉样变性即使在一个家族内临床表型的多变性，以及在这种情况下精确的原纤维分型对正确治疗的重要性。
