Rahhal Samar, Farmer Cristan, Thurm Audrey, Wassif Christopher A, Cawley Niamh X, Perreault John, Dang Do An, Bianconi Simona, Hannah-Shmouni Fady, Guthrie Whitney, Cubit Laura S, Miller Judith S, Sutton V Reid, Koeberl Dwight, Porter Forbes D
Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA.
Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD, USA.
Mol Genet Metab Rep. 2023 Aug 21;37:101001. doi: 10.1016/j.ymgmr.2023.101001. eCollection 2023 Dec.
Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized.
Cerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aβ40, Aβ42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score.
CSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [(32) = 4.05, = 0.0003], Aβ40 [(31) = 6.11, < 0.0001], and Aβ42 [(32) = 3.20, = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = -0.60 [-0.88, 0.005]; Aβ40: ρ = -0.67 [-0.91, -0.12]; Aβ42: ρ = -0.62 [-0.89, -0.02]).
We describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aβ40, Aβ42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aβ40 and Aβ42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aβ40, Aβ42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.
肌酸转运体缺乏症（CTD）是一种罕见的X连锁肌酸转运障碍疾病，由位于Xq28的致病变异引起。该疾病的特征是发育迟缓，尤其是语言发育迟缓。生物标志物β淀粉样蛋白40（Aβ40）、β淀粉样蛋白42（Aβ42）和总tau蛋白在阿尔茨海默病（AD）中异常，AD是一种常见的神经退行性疾病，其病理特征为含有淀粉样斑块的Aβ肽和tau神经原纤维缠结。尽管CTD会导致神经元能量缺乏，但CTD表型背后的病理过程尚未完全明确。
作为CTD自然史研究的可选部分，收集了脑脊液（CSF）。对CTD患者和年龄匹配的对照样本的脑脊液中Aβ40、Aβ42和总tau蛋白水平进行了定量分析。使用Quanterix SR-X仪器进行Neuro3-Plex酶联免疫分析。采用第三版文兰适应行为量表来确定总体适应行为综合（ABC）标准评分。
分析了12例CTD患者的脑脊液和23例年龄匹配的非CTD对照样本。我们发现，与对照组相比，CTD患者脑脊液中的总tau蛋白水平（F(1,32)=4.05，P=0.0003）、Aβ40水平（F(1,31)=6.11，P<0.0001）和Aβ42水平（F(),32)=3.20，P=0.003）均升高。此外，除了1例被视为异常值的个体外，所有这三种生物标志物均与适应行为评分呈负相关（总tau蛋白：ρ=-0.60[-0.88,0.005]；Aβ40：ρ=-0.67[-0.91,-0.12]；Aβ42：ρ=-0.62[-0.89,-0.02]）。
我们在此描述了CTD患者脑脊液中蛋白质生物标志物升高这一新颖发现。与对照样本相比，CTD患者脑脊液中Aβ40、Aβ42和总tau蛋白显著升高，且这些生物标志物水平的升高与ABC评分呈负相关。我们推测，脑脊液中Aβ40和Aβ42水平升高是由于细胞能量缺乏所致。脑脊液中总tau蛋白水平升高可能表明存在持续的神经元损伤。文兰ABC评分与生物标志物水平升高之间观察到的负相关需要在更大的CTD队列中得到证实；然而，我们观察到CTD患者脑脊液中Aβ40、Aβ42和总tau蛋白水平升高，这可能有助于深入了解导致CTD表型的病理机制，并可能在未来的治疗试验中作为支持性数据发挥作用。
