Mendoza-Santiesteban Carlos E, Palma Jose-Alberto, Hedges Thomas R, Laver Nora V, Farhat Nada, Norcliffe-Kaufmann Lucy, Kaufmann Horacio
New England Eye Center, Tufts Medical Center, Tufts University, Boston, Massachusetts, USA.
Department of Neurology, Dysautonomia Center, NYU Langone Medical Center, New York University, New York, USA.
J Neuropathol Exp Neurol. 2017 Mar 1;76(3):238-244. doi: 10.1093/jnen/nlw118.
Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.
临床数据表明，视神经病变和视网膜神经节细胞丢失是家族性自主神经功能异常患者视力下降的主要原因，但此前尚未得到病理学分析的证实。我们研究了3例受影响患者尸检时获得的6只眼睛的视网膜和视神经。分析包括常规神经组织学以及针对神经丝、细胞色素c氧化酶（COX）和含黑视蛋白的神经节细胞的免疫组织化学。我们观察到视神经颞侧部分轴突大量丢失，而鼻侧部分相对保留；这与1例患者的临床和光学相干断层扫描结果相关。视网膜中央神经节细胞层明显减少，而含黑视蛋白的神经节细胞相对未受影响。视神经颞侧部分的COX染色减少，表明线粒体密度降低。通过电子显微镜观察到轴突肿胀，伴有溶酶体和线粒体退变。这些发现支持这样一种观点，即家族性自主神经功能异常患者存在一种特定的视神经病变和视网膜病变，类似于在其他伴有线粒体功能障碍的视神经病变中所见。这增加了一种可能性，即在这种情况下，由IKBKAP基因突变导致的IkB激酶复合物相关蛋白（IKAP）表达缺陷会影响代谢依赖的视网膜小细胞神经节细胞中的线粒体功能。
