Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. Recent years altered this perception, as a growing number of leukodystrophies was described to have an onset at adult ages. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic Cerebral Amyloid Angiopathy that was found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid–old adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles, and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later on displayed severe degeneration and loss. In addition, despite loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of Cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.

中文翻译：

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显性 CST3 变异导致成人发病的脑白质营养不良，但不伴有淀粉样血管病

脑白质营养不良是罕见的遗传性白质疾病，被认为主要发生在儿童时期。近年来改变了这种看法，因为越来越多的脑白质营养不良被描述为在成年时期发病。尽管如此，许多出现白质变化的成年患者仍然没有得到具体的分子诊断。我们描述了来自 8 个家庭的 16 名患者的一种新型成人发病脑白质营养不良症，这些患者携带 CST3 基因中四种不同的停止增益或移码显性变异之一。临床和放射学特征与先前描述的冰岛脑淀粉样血管病明显不同，后者在 CST3 中携带 p.Leu68Asn 替代的患者中发现。临床表型包括反复发作的偏瘫性偏头痛，伴有短暂性单侧局灶性缺陷以及缓慢进展的运动症状和中老年认知能力下降。此外，在某些情况下，急性起病的临床恶化导致长时间发作，意识下降，甚至过早死亡。放射学上，在典型的好发部位发现了特征性改变，涉及大脑深部白质（不包括脑室周围和直接皮质下边缘）、胼胝体中叶、内囊后肢、小脑中脚、大脑脚，特别是苍白球。两个尸检病例的组织病理学特征并未显示血管病，而是白质的微囊性变性至大囊性变性。星形胶质细胞在早期被激活，后来表现出严重的退化和损失。此外，尽管髓磷脂丢失，但仍观察到部分凋亡的少突胶质细胞数量增加。对 CST3 变体的结构比较表明，Cystatin C 的特定截短可能导致蛋白质更容易聚集，从而导致功能异常。未来的研究需要确认对蛋白质的假设影响并确定细胞水平的病理生理下游事件。