Division of Genetics and Genomics, Boston Children's Hospital and Department of Medicine, Harvard Medical School, 1 Autumn Street #525, Boston, MA, 02115, USA.
Health Informatics Institute, University of South Florida, Tampa, FL, USA.
J Inherit Metab Dis. 2018 Jul;41(4):657-667. doi: 10.1007/s10545-017-0132-5. Epub 2018 Feb 8.
Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.
尿素循环障碍常表现为严重的代谢疾病，尽管进行治疗，仍导致高死亡率和显著的神经心理损害。尿素循环障碍纵向研究是一项收集定期临床随访和神经心理学测试数据的自然史研究。本报告探讨了三种远端疾病（精氨琥珀酸合成酶缺乏症（ASD 或瓜氨酸血症 I 型）、精氨琥珀酸裂解酶缺乏症（ASA 或 ALD）和精氨酸酶缺乏症（ARGD））中生化标志物（氨、谷氨酰胺、精氨酸、瓜氨酸）与主要神经心理学终点之间的关系。对 145 名年龄在 3 岁及以上的研究参与者的实验室结果和神经心理学评估测试分数进行了评估，其中 ASD（n=64）、ASA（n=65）和 ARGD（n=16）。所有组的全量表智商均低于人群平均值 100±15：（ASD=79±24；ASA=71±21；ARGD=65±19）。所有组的视觉表现和运动技能缺陷最大。虽然氨水平仍然是预后生物标志物，但其他生物标志物也可能与神经心理功能同样相关。研究中包含的生物标志物的累积暴露被证明是神经心理结局的高度敏感指标，即使在通常认为有毒的截止水平以下也是如此。神经心理学评估当天获得的生物标志物的血液水平与任何疾病任何领域的功能测量均不相关。累积暴露的重要性支持早期识别，并证实需要对尿素循环障碍中发生的所有生化异常（不仅仅是氨）进行良好控制的管理。
