Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
Ann Neurol. 2019 Apr;85(4):560-573. doi: 10.1002/ana.25433.
Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits.
Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests.
There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers.
Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.
转甲状腺素蛋白（TTR）突变相关家族性淀粉样多发性神经病（FAP）的早期表现为小纤维感觉和自主神经症状。本研究旨在探讨皮肤神经病理作为早期和疾病进展生物标志物的潜力及其与皮肤淀粉样沉积的关系。
对患者和携带者进行皮肤活检，以测量表皮内神经纤维（IENF）密度、结构蛋白基因产物 9.5（PGP9.5）的汗腺神经支配指数和肽能血管活性肠肽（SGII[VIP]）以及皮肤淀粉样指数。根据 FAP 分期评分（0-4 期）评估临床残疾程度来分析这些皮肤病变，并与神经生理学和心理物理学测试进行比较。
共有 70 名 TTR 突变体受试者（22 名携带者和 48 名患者），其中 66 例为 TTR-A97S。根据分期，皮肤神经病变明显不同。在携带者中，皮肤去神经支配和肽能性汗腺去神经支配均明显：（1）IENF 密度从 0 期逐渐降低至 4 期；（2）SGII（VIP）从 1 期到 2 期明显降低。相反，SGII（PGP9.5）在携带者和对照组之间相似，但在 2 期患者中下降。在携带者中皮肤淀粉样物缺失，从 1 期开始可检测到。皮肤淀粉样指数与 SGII（PGP9.5）和分期在多变量混合效应模型中相关。在比较所有测试时，只有 IENF 密度、SGII（PGP9.5）和皮肤淀粉样指数与分期相关，并且 IENF 密度在携带者中具有最高的异常率。
感觉和汗腺神经支配的生物标志物表现出与分期相关的进行性模式，感觉神经退行性变是早期皮肤神经病理学的表现。Ann Neurol 2019;85:560-573.
