VA Medical Center, Albany, NY 12208, USA.
Acta Neuropathol. 2010 Jul;120(1):97-108. doi: 10.1007/s00401-010-0675-0. Epub 2010 Mar 26.
Friedreich's ataxia (FRDA) causes a complex neuropathological phenotype with characteristic lesions of dorsal root ganglia (DRG); dorsal spinal roots; dorsal nuclei of Clarke; spinocerebellar and corticospinal tracts; dentate nuclei; and sensory nerves. This report presents a systematic morphological analysis of sural nerves obtained by autopsy of six patients with genetically confirmed FRDA. The outstanding lesion consisted of lack of myelinated fibers whereas axons were present in normal numbers. On cross-sections, only 11% of all class III-beta-tubulin-positive axons were myelinated in FRDA, contrasting with 36% in normal control nerves. Despite their paucity, thin myelinated fibers assembled compact sheaths containing the peripheral myelin proteins PMP-22, P(0), and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and S100alpha immunocytochemistry. Few S100alpha-immunoreactive cells remained detectable whereas laminin 2 reaction product was abundant. The normal honeycomb-like distribution of laminin 2 around myelinated fibers was replaced by confluent regions of reaction product that enveloped clusters of closely apposed thin axons. Electron microscopy not only confirmed the lack of myelin but also showed abnormal Schwann cells and axons. Ferritin localized to normal Schwann cell cytoplasm. In the sensory nerves of patients with FRDA, the distribution of this protein strongly resembled laminin 2, but there was no net increase of the total ferritin-reactive area. Ferroportin reaction product occurred in all axons of sural nerves in FRDA, which was at variance with dorsal spinal roots. In the pathogenesis of sensory neuropathy in FRDA, two mechanisms are likely: hypomyelination due to faulty interaction between axons and Schwann cells; and slow axonal degeneration. Neurons of DRG, satellite cells, Schwann cells, and axons of sensory nerves and dorsal spinal roots derive from the neural crest, and hypomyelination in FRDA may be attributed to defects of regulation or migration of shared precursor cells. Sural nerves in FRDA showed no convincing change in ferritin and ferroportin, militating against local iron dysmetabolism. The result stands out in contrast to the previously reported changes in dorsal spinal roots of patients with FRDA.
弗里德赖希共济失调症（FRDA）导致复杂的神经病理学表型，具有特征性的背根神经节（DRG）病变；背根脊髓；克拉克背核；脊髓小脑和皮质脊髓束；齿状核；和感觉神经。本报告介绍了对六例经基因证实的 FRDA 患者尸检获得的腓肠神经进行系统形态学分析。突出的病变是缺乏有髓纤维，而轴突数量正常。在横切面上，FRDA 中有髓纤维的 III-β-微管蛋白阳性轴突仅占 11%，而正常对照神经中有 36%。尽管数量很少，但薄髓鞘纤维组装成含有外周髓鞘蛋白 PMP-22、P(0)和髓鞘碱性蛋白的紧密鞘。神经显示出施万细胞的重大改变，通过层粘连蛋白 2 和 S100alpha 免疫细胞化学可明显看出。可检测到的 S100alpha 免疫反应细胞很少，而层粘连蛋白 2 反应产物丰富。正常围绕有髓纤维的蜂窝状层粘连蛋白 2 分布被反应产物的融合区域所取代，该区域包围着紧密相邻的薄轴突簇。电子显微镜不仅证实了缺乏髓鞘，还显示了异常的施万细胞和轴突。铁蛋白定位于正常施万细胞质。在 FRDA 患者的感觉神经中，这种蛋白的分布强烈类似于层粘连蛋白 2，但总铁蛋白反应区域没有明显增加。铁蛋白反应产物出现在 FRDA 腓肠神经的所有轴突中，这与背根脊髓不同。在 FRDA 感觉神经病变的发病机制中，可能存在两种机制：轴突与施万细胞之间相互作用异常导致的脱髓鞘；和缓慢的轴突变性。背根神经节的神经元、卫星细胞、施万细胞以及感觉神经和背根脊髓的轴突均来自神经嵴，FRDA 中的脱髓鞘可能归因于共同前体细胞的调节或迁移缺陷。FRDA 腓肠神经中的铁蛋白和铁蛋白无明显变化，不利于局部铁代谢紊乱。这一结果与之前报道的 FRDA 患者背根脊髓的变化形成鲜明对比。
