PRESIDENTIAL ADDRESS: STUDIES IN THE NEURONAL CEROID‐LIPOFUSCINOSES
PRESIDENTIAL ADDRESS: STUDIES IN THE NEURONAL CEROID‐LIPOFUSCINOSES
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主席讲话：神经元蜡样脂褐质沉积症的研究
DOI：
10.1097/00005072-197401000-00001
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发表时间：
1974
影响因子：
3.2
通讯作者：
W. Zeman
中科院分区：
文献类型：
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作者：
W. Zeman
Klenk 于 1939 年 (19) 报告称，物质 X（现在的神经节苷脂 Ge）在 2 名泰萨克斯病患者的大脑中增加了 12 倍，但在 5 名青少年黑蒙性白痴患者的大脑中没有出现这种增加。然而，神经病理学家、神经学家，甚至遗传学家，被无蒙家庭白痴分类为年龄依赖性变异——这是自闭症思维的一个明显例子——所吸引，不会接受伊克伦克的研究结果。正如克伦克的研究所证明的那样，我们转向替代方案，经过一系列细胞化学研究得出的结论是，在这些患者大脑中积累的所谓脂质实际上是自发荧光脂色素。同样，这种解释很久以前就由 Spielmeyer (29)、Hurst (18) 以及 Sjövall 和 Ericsson (28) 提出。然而，当我在 1959 年提交这些结果发表时，我收到了礼貌但消极的复制品，并解释说我忽略了“掩蔽的、蛋白质结合的神经节苷脂的存储”。虽然我们对青少年黑蒙性白痴患者神经细胞中“储存”的所谓脂质的性质没有什么新的了解，但显而易见的任务是找到其积累的解释。在我们进行适当的研究之前，我们意识到，即使不完全相同，也有一种非常相似的脂色素在乳婴儿黑蒙性白痴患者 (5) 以及成人型 IKufs 患者 (21) 的大脑中积聚。在那个阶段，对文献和我自己对大约 30 名患有这些疾病的患者的观察进行了严格的评估，促使我对家族性黑蒙性白痴进行了重新分类，目的是明确区分一方面是神经节苷脂代谢紊乱的形式，另一方面是自发荧光脂色素积累的形式（表 1）。在回答为什么我对 Batten-Mayou 和 Spielmeycr-Vogt 类型进行分类的问题时，我应该指出 Vogt (35) 以及 Battcn 和 Miayou (4) 并没有区分晚期婴儿类型和青少年类型；他们的各种出版物都描述了两者，就好像它们是相同的一样。因此，我们引入了巴顿-沃格特综合征这一名称，作为神经元蜡样脂褐质沉着症的同义词。黑蒙白痴的疾病分类概念的历史演变已在其他地方详细描述（37）。随后，我们开始对 Van Bagh 和 Hordling 发现的淋巴细胞空泡化这一表观遗传标记进行系统研究 (3)，并显示该标记存在于纯合子和杂合子个体中。斯特劳斯并没有能够证实这种变化的不变性，而雷纳（Rayner）（25）在大量家族中如此热情地记录了这种变化的不变性，斯特劳斯（Strouth）发现了多形核中性粒细胞（31）的特殊嗜天青性过度颗粒化，它也通过分离为孟德尔显性细胞（23）而成为遗传标记，但仅在部分亲缘中存在。与此同时，我们积累了大量脑活检和尸检标本用于电子显微镜研究，很明显，神经元内色素在超微结构上与 Terry 和 Korey (33) 刚刚在泰萨克斯病中证明的器官细胞有很大不同。我们也无法在患有这种疾病的患者中找到白细胞标记物
Klenk in 1939 (19) when he reported that substance X, today ganglioside Ge, was increased twelvefold in 2 brains of patients with Tay-Sachs diseasc but no such increase was present in 5 brains of paticnts with juvenile amaurotic idiocy. Nevertheless, neuropathologists, neurologists and even geneticists, lured by thc intellectually pleasing classification of amaurotic family idiocy into agedependent variants-a clear-cut instance of autistic thinking–would not acccpt IKlenk's findings. As or studics provcd Klenk correct, we tırncd to alternativcs and after a series of cytochcnical studies arrived at the conclusion that the so-callcd lipids which accumulate in thc brains of these paticnts are actually autofluorescent lipopigments. Again, this interpretation liad long before been proposed by Spielmeyer (29), Hurst (18), and by Sjövall and Ericsson (28). However, when I submitted these results for publication in 1959, I receivcd polite but negative replics with thc explanation that I had overlooked the “storage of masked, protein-bound gangliosides”. Whilc we lıad nothing new to offer as regards the nature of the so-called lipids “stored” in the nerve cells of patients with juvenile amaurotic idiocy, the obvious task was to find an explanation for their accumulation. Before we got appropriate studies underway, we realizcd tlıat a very similar, if not identical, lipopigment accumulates also in the brains of patients with latc infantile amaurotic idiocy (5) as well as in the adult typc of IKufs (21). At that stage a critical cvaluation of the literature and of my own observations on about 30 patients with these disorders prompted me to reclassify the familial amaurotic idiocies with the aim of clearly distinguishing between forms with a disturbance of ganglioside metabolisın on the one hand and those with an accumulation of autofluorescent lipopigments on the other (Table 1). In answer to the question as to why I climinated tlhe Batten-Mayou and thc Spielmeycr-Vogt types, I should point out that Vogt (35) and Battcn and MIayou (4) did not distinguislı between the late infantile and the juvenile types; their various pulblications describe both, as if they were identical. Consequently, we introluced the designation Batten-Vogt syndrome as synonymous with neuronal ceroid-lipofuscinosis. The historical cvolution of the nosological concept of the amaurotic idiocies has lcen detailed elsewhere (37). Subsequently, we embarked on a systematic study of the apparent genetic marker, lymphocytic vacuolization, discovered by Van Bagh and Hortling (3) and shown to be present in both homozygous and heterozygous individuals. Instead of bcing able to confirm the invariance of this change which had been so zealously documented by Rayner (25) on a large number of families, Strouth discovered a peculiar azurophilic hypergranulation of the polymorphonuclear neutrophils (31), which also lchaved as a genetic marker by segregating as a Mendelian dominant (23), but only in a part of tlıe kindreds. In the meantime we had accumulated a sizable collection of brain biopsy and autopsy specimens for electron microscopic studies and it became clear that the intraneuronal pigments were ultrastructurally quite different from the organ-clles which Terry and Korey (33) had just demonstrated in Tay-Sachs disease. Nor could we find the leukocytic markers in patients with this