Sen Kuntal, Anderson Afrouz A, Whitehead Matthew T, Gropman Andrea L
Division of Neurogenetics and Neurodevelopmental Pediatrics, Department of Neurology, Children's National Hospital, George Washington University School of Medicine, Washington, DC, United States.
Department of Research, Focus Foundation, Crofton, MD, United States.
Front Neurol. 2021 Apr 28;12:632307. doi: 10.3389/fneur.2021.632307. eCollection 2021.
The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.
尿素循环障碍（UCD）是一种罕见的遗传性疾病，病因是六种酶或两种转运蛋白中的一种缺乏，这些酶和转运蛋白的作用是将体内氨形式的废氮排出。在本综述中，我们重点关注鸟氨酸转氨甲酰酶缺乏症（OTCD）和精氨酸酶缺乏症的神经影像学研究，这是我们广泛研究的两种UCD。鸟氨酸转氨甲酰酶缺乏症（OTCD）是其中最常见的，且为X连锁。OTCD中的高氨血症（HA）是由于蛋白质处理缺陷所致。认知障碍和神经行为障碍已成为精氨酸酶缺乏症和OTCD的主要后遗症，尤其是与执行功能和工作记忆有关，影响前额叶皮质（PFC）。临床管理的重点是预防HA导致的神经保护以及其他已知和未知代谢物的神经毒性。预防和减轻神经损伤是一项重大挑战和研究重点。鉴于HA对UCD神经认知功能的影响，神经影像学方法，尤其是多模态成像平台，可以提供大量信息来了解神经认知功能和生物标志物。这些信息可以进一步改善临床决策，并带来更好的治疗干预。使用多模态神经影像学结合临床和行为表型对受影响的大脑进行研究具有前景。磁共振波谱已经被证明是一种研究生化异常的工具，例如HA周围谷氨酰胺升高，以及诊断部分UCD。功能近红外光谱（fNIRS）可评估皮质区域脑血流动力学水平的局部变化，正在成为一种非侵入性技术，并将作为功能磁共振成像的替代方法，具有更好的便携性。在这里，我们回顾了二十年来我们使用非侵入性成像的研究，以及它如何有助于理解这组遗传疾病的认知影响。
