Abstract：
The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN.
Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls.
In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants.
These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype.
Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.
Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls.
In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants.
These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype.
Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.
摘要：
目的：遗传疗法彻底改变了遗传性甲状腺素运载蛋白淀粉样变性多发性神经病（ATTRv-PN）的治疗方法，显著改善患者的预后。虽然治疗开始的最佳时机仍然未知，早期治疗是可取的。因此,本研究的目的是开发ATTRv-PN早期神经功能障碍的生物标志物.
方法：对22例致病性遗传性转甲状腺素蛋白淀粉样蛋白（ATTRv）基因变异患者进行了尺骨运动和感觉轴突兴奋性研究，12例有大纤维神经病变(LF+)，10例无纤维神经病变(LF-)，与年龄和性别匹配的健康对照相比。
结果：在运动轴突中，我们发现了健康对照组的连续变化，对于LF-和LFATTRv，超极化阈值电调逐渐降低（TEh40（10-20ms）：p=0.04，TEh40（20-40ms）：p=0.01和TEh40（90-10ms）：p=0.01），提示膜去极化。在感觉轴突中，在LF（SubEx）和双脉冲（SubEx2）恢复循环测试中观察到较低水平的亚兴奋性（SubEx：p=0.015，SubEx2：p=0.015，RC（2-1）：p=0.04）表明降低的节点慢电导钾，促进感觉过度兴奋，感觉异常和疼痛。比较不同的ATTRv变体时，感觉或运动兴奋性参数没有差异。
结论：在ATTRv-PN的疾病谱中观察到的这些进行性变化表明轴突兴奋性对于识别ATTRv的早期和进行性神经功能障碍具有实用性。无论基因型。
结论：轴突兴奋性是ATTRv-PN神经功能障碍的早期生物标志物。
方法：对22例致病性遗传性转甲状腺素蛋白淀粉样蛋白（ATTRv）基因变异患者进行了尺骨运动和感觉轴突兴奋性研究，12例有大纤维神经病变(LF+)，10例无纤维神经病变(LF-)，与年龄和性别匹配的健康对照相比。
结果：在运动轴突中，我们发现了健康对照组的连续变化，对于LF-和LFATTRv，超极化阈值电调逐渐降低（TEh40（10-20ms）：p=0.04，TEh40（20-40ms）：p=0.01和TEh40（90-10ms）：p=0.01），提示膜去极化。在感觉轴突中，在LF（SubEx）和双脉冲（SubEx2）恢复循环测试中观察到较低水平的亚兴奋性（SubEx：p=0.015，SubEx2：p=0.015，RC（2-1）：p=0.04）表明降低的节点慢电导钾，促进感觉过度兴奋，感觉异常和疼痛。比较不同的ATTRv变体时，感觉或运动兴奋性参数没有差异。
结论：在ATTRv-PN的疾病谱中观察到的这些进行性变化表明轴突兴奋性对于识别ATTRv的早期和进行性神经功能障碍具有实用性。无论基因型。
结论：轴突兴奋性是ATTRv-PN神经功能障碍的早期生物标志物。
