The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyse brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice.

中文翻译：

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人和鼠急性间歇性卟啉症的脑室扩大。

严重急性间歇性卟啉症（AIP）患者中枢神经系统发生的形态学变化尚未明确。这项工作的目的是分析没有癫痫发作或临床后部可逆性脑病综合征的严重 AIP 患者的大脑受累情况，以及接受或不接受旨在纠正代谢紊乱的肝脏导向基因治疗的小鼠模型。我们对 8 名严重受影响的患者（6 名女性）和 16 名性别和年龄匹配的对照组进行了神经放射学研究。在获得灌注成像数据的两名患者的急​​性发作期间，七名患者表现出脑室显着扩大和脑灌注减少。即使在卟啉前体略微增加的情况下，AIP 小鼠也表现出脑血流量减少和脑室慢性扩张。虽然苯巴比妥引起的反复发作会加剧 AIP 小鼠的心室扩张，但使用肝脏导向基因疗法纠正代谢缺陷可恢复脑灌注并防止心室扩大。组织学研究显示没有神经元丢失的迹象，但脑室周围区域有更密集的神经丝模式，这表明压迫可能是由脑脊液动力学失衡引起的。总之，严重受影响的 AIP 患者表现出脑室扩大。肝脏导向的基因治疗可以防止 AIP 小鼠大脑中出现的疾病的形态学后果。