转甲状腺素蛋白相关家族性淀粉样变性多发性神经病的临床、遗传学特点及随访研究

Clinical,genetic characteristics and follow-up in 14 patients with transthyretin familial amyloid polyneuropathy

目的总结转甲状腺素蛋白相关家族性淀粉样变性多发性神经病(TTR-FAP)患者的临床、遗传学及预后特点。方法收集2014年9月至2022年2月于首都医科大学宣武医院神经内科确诊的无亲缘关系的14例TTR-FAP患者,对其临床表现、神经电生理、心脏功能、活组织检查病理、基因突变类型及预后进行分析。结果14例TTR-FAP患者中,男性13例,女性1例,平均发病年龄53.9岁(范围:33.0~71.0岁),起病至确诊的平均病程为4.1年,9例为晚发型,7例有阳性家族史。首发症状中,8例有双下肢远端感觉障碍,4例有上肢、四肢或单个肢体感觉运动障碍,2例有胃肠自主神经功能障碍。随疾病进展,感觉性或感觉运动性周围神经病和自主神经功能障碍是最常见的临床表现。多数患者就诊时无心脏受累明显症状,但9/13的患者心电图异常,6/8的患者存在左心室肥厚。神经传导测定结果显示四肢感觉、运动纤维以轴索损害为著,伴不同程度脱髓鞘病变。腓肠神经活组织检查镜下可见有髓神经纤维密度呈中至重度丢失,刚果红染色阳性率8/14。在发现的8种TTR基因突变类型中,V50M最为常见(出现于5例患者中)。5例患者使用氯苯唑酸治疗后疾病无明显进展,2例于发病后8、12年死于恶液质。结论TTR-FAP多见于男性,以感觉运动轴索性周围神经病、自主神经功能障碍和心脏亚临床损害为主要临床表现,V50M是本组患者最常见的致病突变,氯苯唑酸可延缓疾病进展。

Objective To summarize the clinical and genetic characteristics in patients with transthyretin familial amyloid polyneuropathy(TTR-FAP).Methods Fourteen unrelated TTR-FAP patients diagnosed at Xuanwu Hospital,Capital Medical University from September 2014 to February 2022 were retrospectively reviewed.The clinical manifestation,electrophysiology,cardiac function,biopsy and gene mutation were analyzed.Results In the 14 patients(13 males,1 female)diagnosed as TTR-FAP,the mean age at onset was 53.9 years(range:33.0-71.0 years),with a mean course from symptom-onset to diagnosis of 4.1 years.The late-onset type occurred in 9 cases.Seven patients had a family history of TTR-FAP.Distal paresthesia of lower limbs was the commonest initial symptom(8 cases),with sensorimotor neuropathy and autonomic dysfunction seen initially in 4 and 2 cases,respectively.Cardiac involvement occurred in 6/8 of the patients.Nerve conduction studies indicated extremely axonal impairment with demyelinating features.Sural nerve biopsies showed moderate to severe axonal loss of myelinated fibers and the positive rate of Congo red staining was 8/14.Of 8 different TTR mutations detected,V50M was the most common(appearing in 5 cases).No obvious neuropathy progression was seen in the 5 patients who received tafamidis and 2 patients died of dyscrasia.Conclusions TTR-FAP is more common in males,with sensorimotor axonal polyneuropathy,autonomic dysfunction and cardiac subclinical damage as the predominant symptoms.V50M is the commonest mutation.Tafamidis can delay the progression of disability.