Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C
Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C
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DOI：
10.1111/neup.12380
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发表时间：
2017-10-01
期刊：
影响因子：
2.3
通讯作者：
Yamagata, Takanori
中科院分区：
文献类型：
--
作者：
Kodachi, Tsuyoshi;Matsumoto, Shizuko;Yamagata, Takanori
C型尼曼-匹克病（NPC）是一种由细胞胆固醇转运缺陷引起的胆固醇储存病。NPC的发病和进展是可变的，尸检结果主要报告了这种疾病的成人和青少年形式。我们报告一位9岁女性患者，因NPC 1基因突变而罹患晚期婴儿型鼻咽癌。她在4个月大时有明显的脾肿大。她在18个月大时失去了说话的能力。她学会了走路，但经常摔倒，30个月后再也不能走路了。3岁时，她被诊断为NPC。NPC 1基因的序列分析显示T2108 C（F703 S）和C2348 G（S813 X）的复合杂合突变（均为新突变）。此后，患者反复呼吸道感染，9岁时死于呼吸衰竭。病理学发现包括脑萎缩（特别是白色物质）、重度脱髓鞘以及大脑和脑干核的神经元丢失。大脑、小脑和脑干中残留的神经元细胞和小胶质细胞肿胀并呈泡沫状。海马CA 1区和浦肯野细胞的神经元相对较少，不存在老年斑和轴突球体。在其他器官中也观察到泡沫细胞，尤其是脾脏和骨髓。该患者的F703 S突变位于固醇敏感结构域（SSD）。严重的神经系统表型先前已报告在SSD错义突变的患者。我们认为SSD中的无义突变和错义突变的组合是导致我们目前患者的严重神经系统表型的原因。虽然成人/青少年形式的NPC的病理学发现包括肿胀的神经元和神经胶质、神经元细胞损失和NFT，但脱髓鞘可能是婴儿形式的NPC的主要发现。
Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18months of age. She learned to walk, but often fell and could no longer walk after 30months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.