Clinic for Special Children, 535 Bunker Hill Road, Strasburg, PA 17579, USA.
Brain. 2010 Jan;133(Pt 1):76-92. doi: 10.1093/brain/awp297. Epub 2009 Dec 23.
In glutaric aciduria type 1, glutaryl-coenzyme A and its derivatives are produced from intracerebral lysine and entrapped at high concentrations within the brain, where they interfere with energy metabolism. Biochemical toxicity is thought to trigger stroke-like striatal degeneration in susceptible children under 2 years of age. Here, we explore vascular derangements that might also contribute to brain damage. We studied injured and non-injured Amish glutaric aciduria type 1 patients using magnetic resonance imaging (n = 26), transcranial Doppler ultrasound (n = 35) and perfusion computed tomography (n = 6). All glutaric aciduria type 1 patients had wide middle cerebral, internal carotid and basilar arteries. In non-injured patients, middle cerebral artery velocities were 18-26% below control values throughout late infancy and early childhood, whereas brain-injured children had an early velocity peak (18 months) and low values thereafter. Perfusion scans from six patients showed that tissue blood flow did not undergo a normal developmental surge. We observed four different perfusion patterns. (i) Three children (two non-injured) had low cerebral blood flow, prolonged mean transit time, elevated cerebral blood volume and high mean transit time/cerebral blood flow and cerebral blood volume/cerebral blood flow ratios. This pattern optimizes substrate extraction at any given flow rate but indicates low perfusion pressure and limited autoregulatory reserve. (ii) Ten hours after the onset of striatal necrosis in an 8-month-old infant, mean transit time and cerebral blood volume were low relative to cerebral blood flow, which varied markedly from region to region. This pattern indicates disturbed autoregulation, regional perfusion pressure gradients, or redistribution of flow from functional capillaries to non-exchanging vessels. (iii) In an infant with atrophic putaminal lesions, striatal flow was normal but mean transit time and cerebral blood volume were low, consistent with perfusion in excess of metabolic demand. (iv) Finally, a brain-injured adult with glutaric aciduria type 1 had regional perfusion values within the normal range, but the putamina, which normally have the highest regional perfusion, had cerebral blood flow values 24% below cortical grey matter. Although metabolic toxicity appears central to the pathophysiology of striatal necrosis, cerebrovascular changes probably also contribute to the process. These changes may be the primary cause of expanded cerebrospinal fluid volume in newborns, intracranial and retinal haemorrhages in infants and interstitial white matter oedema in children and adults. This pilot study suggests important new areas for clinical investigation.
在 1 型戊二酸血症中，谷氨酸辅酶 A 及其衍生物由脑内赖氨酸产生，并在大脑内被高浓度截留，从而干扰能量代谢。生化毒性被认为会在 2 岁以下易感儿童中引发类似中风的纹状体变性。在这里，我们探讨了可能也有助于脑损伤的血管异常。我们使用磁共振成像（n = 26）、经颅多普勒超声（n = 35）和灌注计算机断层扫描（n = 6）研究了受伤和未受伤的阿米什 1 型戊二酸血症患者。所有 1 型戊二酸血症患者的大脑中动脉、颈内动脉和基底动脉均较宽。在未受伤的患者中，大脑中动脉的速度在婴儿后期和幼儿期一直低于对照值 18-26%，而脑损伤的儿童则有一个早期的速度峰值（18 个月），之后速度值较低。来自 6 名患者的灌注扫描显示，组织血流未经历正常的发育性激增。我们观察到四种不同的灌注模式。（i）三名儿童（两名未受伤）的脑血流低，平均通过时间延长，脑血容量增加，平均通过时间/脑血流和脑血容量/脑血流比值升高。这种模式在任何给定的血流速率下都能优化底物提取，但表明灌注压力低且自动调节储备有限。（ii）在一名 8 个月大婴儿纹状体坏死发作 10 小时后，与脑血流相比，平均通过时间和脑血容量较低，脑血流在不同区域之间差异很大。这种模式表明自动调节紊乱、区域灌注压力梯度或血流从功能毛细血管重新分布到非交换血管。（iii）在一名有萎缩性壳核病变的婴儿中，纹状体血流正常，但平均通过时间和脑血容量较低，与代谢需求过剩的灌注一致。（iv）最后，一名患有 1 型戊二酸血症的脑损伤成人的区域灌注值在正常范围内，但正常情况下具有最高区域灌注的壳核的脑血流值比皮质灰质低 24%。虽然代谢毒性似乎是纹状体坏死病理生理学的核心，但脑血管变化可能也对该过程有贡献。这些变化可能是新生儿扩大的脑脊液体积、婴儿颅内和视网膜出血以及儿童和成人的间质性脑白质水肿的主要原因。这项初步研究为临床研究提供了重要的新领域。
