Inborn errors of metabolism (IEM) involving the non-oxidative pentose phosphate pathway (PPP) include the two relatively rare conditions, transketolase deficiency and transaldolase deficiency, both of which can be difficult to diagnosis given their non-specific clinical presentations. Current biochemical testing approaches require an index of suspicion to consider targeted urine polyol testing. To determine whether a broad-spectrum biochemical test could accurately identify a specific metabolic pattern defining IEMs of the non-oxidative PPP, we employed the use of clinical metabolomic profiling as an unbiased novel approach to diagnosis.

Subjects with molecularly confirmed IEMs of the PPP were included in this study. Targeted quantitative analysis of polyols in urine and plasma samples was accomplished with chromatography and mass spectrometry. Semi-quantitative unbiased metabolomic analysis of urine and plasma samples was achieved by assessing small molecules via liquid chromatography and high-resolution mass spectrometry. Results from untargeted and targeted analyses were then compared and analyzed for diagnostic acuity.

Two siblings with transketolase (TKT) deficiency and three unrelated individuals with transaldolase (TALDO) deficiency were identified for inclusion in the study. For both IEMs, targeted polyol testing and untargeted metabolomic testing on urine and/or plasma samples identified typical perturbations of the respective disorder. Additionally, untargeted metabolomic testing revealed elevations in other PPP metabolites not typically measured with targeted polyol testing, including ribonate, ribose, and erythronate for TKT deficiency and ribonate, erythronate, and sedoheptulose 7-phosphate in TALDO deficiency. Non-PPP alternations were also noted involving tryptophan, purine, and pyrimidine metabolism for both TKT and TALDO deficient patients.

Targeted polyol testing and untargeted metabolomic testing methods were both able to identify specific biochemical patterns indicative of TKT and TALDO deficiency in both plasma and urine samples. In addition, untargeted metabolomics was able to identify novel biomarkers, thereby expanding the current knowledge of both conditions and providing further insight into potential underlying pathophysiological mechanisms. Furthermore, untargeted metabolomic testing offers the advantage of having a single effective biochemical screening test for identification of rare IEMs, like TKT and TALDO deficiencies, that may otherwise go undiagnosed due to their generally non-specific clinical presentations.

涉及非氧化戊糖磷酸途径 (PPP) 的先天性代谢缺陷 (IEM) 包括两种相对罕见的疾病，转酮醇酶缺乏症和转醛醇酶缺乏症，鉴于其非特异性临床表现，这两种疾病都难以诊断。当前的生化检测方法需要怀疑指数才能考虑进行针对性的尿液多元醇检测。为了确定广谱生化测试是否可以准确识别定义非氧化 PPP 的 IEM 的特定代谢模式，我们采用临床代谢组学分析作为一种公正的新诊断方法。

本研究包括具有分子确认的 PPP IEM 的受试者。尿液和血浆样品中多元醇的目标定量分析是通过色谱法和质谱法完成的。通过液相色谱法和高分辨率质谱法评估小分子，实现了尿液和血浆样品的半定量无偏代谢组学分析。然后比较非靶向分析和靶向分析的结果并分析诊断敏锐度。

确定了两名患有转酮醇酶 (TKT) 缺乏症的兄弟姐妹和三名患有转醛醇酶 (TALDO) 缺乏症的无关个体，以纳入研究。对于这两种 IEM，针对尿液和/或血浆样本的靶向多元醇测试和非靶向代谢组学测试确定了各自疾病的典型扰动。此外，非靶向代谢组学测试揭示了其他 PPP 代谢物的升高，这些代谢物通常无法通过靶向多元醇测试进行测量，包括 TKT 缺乏症的核糖酸、核糖和赤酮酸，以及 TALDO 缺乏症的核糖酸、赤酮酸和 7-磷酸景天酮。对于 TKT 和 TALDO 缺陷患者，还注意到涉及色氨酸、嘌呤和嘧啶代谢的非 PPP 变化。

靶向多元醇测试和非靶向代谢组学测试方法都能够识别出表明血浆和尿液样本中 TKT 和 TALDO 缺乏症的特定生化模式。此外，非靶向代谢组学能够识别新的生物标志物，从而扩展对这两种疾病的当前知识，并进一步深入了解潜在的潜在病理生理机制。此外，非靶向代谢组学测试提供了一个优势，即通过单一有效的生化筛查测试来识别罕见的 IEM，如 TKT 和 TALDO 缺陷，否则可能由于其通常非特异性的临床表现而无法确诊。