Department of Neurology, Wayne State University, Detroit 48201, USA.
Brain. 2009 Dec;132(Pt 12):3263-73. doi: 10.1093/brain/awp274.
Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.
腓骨肌萎缩症 1A 型是最常见的遗传性周围神经病，由 17p11.2 染色体重复引起，该区域包含外周髓鞘蛋白 22 基因。这种疾病的特征是传导速度均匀减慢和继发轴突丢失，与获得性脱髓鞘疾病（如慢性炎症性脱髓鞘性多发性神经病）的传导速度不均匀减慢形成对比。腓骨肌萎缩症 1A 型传导速度减慢和轴突丢失的机制尚不清楚，部分原因是由于神经活检的侵袭性，难以从患者身上获得神经样本。我们利用无毛皮肤活检，一种微创程序，在腓骨肌萎缩症 1A 型患者（n=32）、慢性炎症性脱髓鞘性多发性神经病患者（n=4）和健康对照者（n=12）中系统地评估这些问题。使用免疫组织化学和电子显微镜检查皮肤有髓神经纤维的形态和分子结构。与正常对照组相比，腓骨肌萎缩症 1A 型患者的节段性脱髓鞘缺失（P<0.0001），但所有慢性炎症性脱髓鞘性多发性神经病患者均存在节段性脱髓鞘。使用 Meissner 小体的密度可以测量轴突丢失，并与轴内堆积的线粒体相关。我们的研究表明，皮肤活检可以揭示区分遗传性和获得性脱髓鞘神经病的病理和分子结构改变。腓骨肌萎缩症 1A 型的均匀缩短的节间长度表明节间延长的潜在发育缺陷。线粒体在轴内的堆积为腓骨肌萎缩症 1A 型轴突变性的发病机制提供了新的见解。
