Biomarkers of Neurological Injury and Recovery in Urea Cycle Disorders

在近端尿素循环障碍(UCD)中，尤其是鸟氨酸转氨酶缺乏症(OTCD)，高氨血症(HA)导致脑谷氨酰胺(Gin)升高，这种紊乱被认为是神经损伤的核心。相比之下，在远端尿毒症，如瓜氨酸血症(精氨酸琥珀酸合酶缺乏症；(ASD)和argininosuccinicaciduria(argininosuccinatelyase缺乏症)；(ASLD)认知障碍和神经精神疾病即使在没有急性HA的情况下也很常见。因此，瓜氨酸和精氨酸琥珀酸(ASA)或它们的代谢产物都被认为具有神经毒性。在这个项目中，我们将使用最先进的神经成像和神经心理学方法来调查OTCD患者是否存在与局部脑结构异常和神经认知功能障碍相关的慢性脑Gin升高和肌醇(ML)水平下降。我们将进一步研究在HA急性发作期间，脑内Gin升高和ML降低是否与细胞毒性水肿的程度相关，以及是否可以确定细胞毒性水肿之后细胞丢失的谷氨酰胺/ml比值阈值。最后，将调查ASSD和/或ASLD的脑损伤区域是否与OTCD的脑损伤区域不同，并比较无HA的ASD和ASLD与OTCD的脑Gin水平。我们还将寻求确定是否可以在UCD远端患者的大脑中发现脑瓜氨酸和ASA，以及它们是否与MRI和神经心理测试中看到的脑异常相关。本项目将阐明急性高氨血症和慢性UCD的脑病理年表，以及UCD近端和远端在脑损伤的病理生理学上是否有所不同。

In proximal urea cycle disorders (UCD), particularlyornithine transcarbamylase deficiency (OTCD), hyperammonemia (HA) causes increased brain glutamine (Gin) which perturbation is thoughtto be at the core of the neurological injury. In contrast, in distal UCD such as citrullinemia(argininosuccinatesynthetase deficiency; (ASSD) and argininosuccinicaciduria(argininosuccinatelyase deficiency); (ASLD) cognitive impairment and neuropsychiatric disease are common even in the absence of acute HA. As a consequence, both citrulline and argininosuccinate (ASA) or their metabolic products have been implicated as neurotoxic. In this project we will use state-of- the-art neuroimaging and neuropsychological methods to investigate whether patients with OTCD have chronically elevated brain Gin and reduced myo-inositol (ml) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction. We will further investigate whether during an acute episode of HA elevated brain Gin and decreased ml levels correlate with the magnitude of cytotoxic edema and whether a Gln/ml ratio threshold can be identified at which the cytotoxic edema is followed by cell loss. Finally, will investigate whether regions of brain damage in ASSD and/or ASLD are distinct from those in OTCD and compare brain Gin levels in ASSD and ASLD in the absence of HA to those in OTCD. We will also seek to determine if brain citrulline and ASA can be identified in the brains of patients with distal UCD and whether they correlate with brain abnormalities seen in MRI and neuropsychological testing. This project will elucidate the chronology of brain pathology both in acute hyperammonemia and chronic UCD and whether, proximal and distal UCD differ in their pathophysiology of brain damage.