家族性淀粉样变性多神经病--附一家系临床、病理和分子遗传学研究

目的：报道一个家族性淀粉样变性多神经病家族的临床特点、病理改变和基因检测结果。方法：先证者为52岁女性患者，于7年前反复出现恶心和呕吐，6年前出现便秘。5年前开始逐渐出现双下肢麻木伴出汗减少。3年前逐渐出现双侧下肢无力伴随肌肉萎缩，皮肤出现红色丘疹伴随瘙痒，2年前出现无痛性腹泻，从卧位站立时明显头晕。家族中患者的两个儿子分别在16岁和22岁出现反复的腹泻和手足麻木，妹妹、父亲和叔叔均出现类似临床表现。对先证者做左侧腓肠神经活检，并进行常规光镜和电镜检查，应用抗免疫球蛋白κ-和λ-链抗体以及抗tranthyretin(TTR)抗体进行免疫组织化学染色。提取先证者及其长子的外周血白细胞DNA，进行TTR及apolipoproteinA1基因的突变检测。结果：病理检查发现神经束内刚果红阳性物质沉积在血管周围并对神经纤维造成挤压。电镜检查显示小沉积物由大量的细丝组成。神经束内有髓和无髓神经纤维显著减少。免疫组化检查显示沉积物抗免疫球蛋白κ-和λ-链抗体以及抗TTR抗体均为阴性染色。分子遗传学检查显示先证者及其长子的TTR基因的所有4个外显子和apolipoproteinA1基因的所有外显子均未发现任何突变。结论：患者的病理改变符合系统性类淀粉变性周围神经病，结合遗传特点和临床表现考虑为家族性显性遗传性类淀粉周围神经病，但免疫组化和分子生物学结果不能进一步确定其分类。我们推测此家族可能是显性遗传性类淀粉周围神经病的一个新类型。

Clinical pathology and molecular genetics on familial amyloidotic polyneuropathy

OBJECTIVE: To report the clinical, pathologic and molecular genetic features of a Chinese family with familial amyloidotic polyneuropathy (FAP) in Beijing area. METHODS: The proband was a 52-year-old woman with 7 years history of vomitting and diarrhea and weakness as well as anaesthesia. In her family there were 5 patients with initial presentation in three consecutive generations ranging in age from 21 to 45 years. Sensory neuropathy and systemic autonomic symptoms appeared in all the 5 patients, with muscle weakness in 2 cases in the later stage of disease. Gastrointestinal involvement appeared in the early stage of disease in all patients. Sural nerve biopsy was performed on the proband. The nerve specimens were applied for routine histological and ultrastructural investigation as well as immuno-histochemical staining with monoclonal antibodies against transthyretin (TTR) protein, immunoglobulin kappa- and lambda-chains. DNA analysis was performed on the proband and her son for TTR gene and apolopoprotein A1. RESULTS: Amyloid, identified as amorphous eosinophilic extracellular deposits on Congo red staining and recognized by its characteristic fibrillar ultrastructure with electron microscopy, was identified arround small vessel in the endoneurium. Axonal loss was recorded as severe (> 75%). Immunoglobulin kappa- and lambda-chains as well as TTR positive deposits were not demonstrated in the accumulated amyloid material. There was neither TTR nor apolopoprotein A1 coding gene mutation detected in the proband and her son. CONCLUSION: The pathological findings demonstrated existence of a FAP. However, the immuno-pathological and genetic results could not classified the type of this FAP family. Further genetic studies are required to identify it.