Objective

The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals.

Methods

In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype.

Results

Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis.

Conclusion

Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.

中文翻译：

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新生儿筛查对胞质尿素循环障碍个体代谢病程的严重程度调整评估

 客观的

针对 1 型瓜氨酸血症 (CTLN1) 和精氨基琥珀酸尿症 (ASA) 的新生儿筛查 (NBS) 计划的实施存在争议。本研究的目的是评估 NBS 对受影响个体的代谢性疾病病程和临床结果的影响。

 方法

在 115 名患有 CTLN1 和 ASA 的个体中，我们将初始高氨血症发作 (HAE) 的严重程度和（后续）HAE 的频率与诊断模式进行了比较。根据最近建立的功能性疾病预测模型，根据预测的严重或减毒表型对个体进行分层。

 结果

与出现症状后确定的个体相比，NBS 组中具有预测的 CTLN1 和 ASA 减毒形式的个体比例过高，而具有预测的严重表型的个体比例不足 (SX)。 NBS 的识别与预测的严重表型和减毒表型个体中初始 HAE 严重程度的降低相关，但与（随后的）HAE 频率降低无关。当将一些症状前诊断的患者（即产前检测和高危家庭筛查）纳入本分析时，也得到了类似的结果。

 结论

由于 NBS 结果研究的主要挑战之一是 NBS 队列中预测减毒表型的个体可能过多，因此对筛选和未筛选个体进行严重程度调整评估对于避免高估 NBS 效应非常重要。 NBS 能够减弱 CTLN1 和 ASA 患者最初的 HAE，但不会影响随后代谢失代偿的频率。未来的长期研究需要评估这一发现的临床影响，特别是在死亡率、认知结果和幸存者的生活质量方面。