Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by a deficiency in sphingosine-1-phosphate lyase (SPL), the final enzyme in the sphingolipid degradative pathway. Inactivating mutations of SGPL1—the gene encoding SPL—lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease. Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown. In this report, we describe the correlation between SGPL1 genotypes, age at diagnosis, and patient outcome. Vitamin B6 serves as a cofactor for SPL. B6 supplementation may aid some SPLIS patients by overcoming poor binding kinetics and promoting proper folding and stability of mutant SPL proteins. However, this approach remains limited to patients with a susceptible allele. Gene therapy represents a potential targeted therapy for SPLIS patients harboring B6-unresponsive missense mutations, truncations, deletions, and splice-site mutations. When Sgpl1 knockout (SPL^KO) mice that model SPLIS were treated with adeno-associated virus (AAV)-mediated SGPL1 gene therapy, they showed profound improvement in survival and kidney and neurological function compared to untreated SPL^KO mice. Thus, gene therapy appears promising as a universal, potentially curative treatment for SPLIS.

1-磷酸鞘氨醇裂解酶不足综合征 (SPLIS) 是一种罕见的代谢性疾病，由 1-磷酸鞘氨醇裂解酶 (SPL) 缺陷引起，SPL 是鞘脂降解途径中的最终酶。 SGPL1 （编码 SPL 的基因）的失活突变导致其下游产物的缺乏，以及鞘脂中间体的积累，包括其生物活性底物 1-磷酸鞘氨醇 (S1P)，后者导致淋巴细胞减少，这是该疾病的一个标志。 SPLIS 的其他表现包括肾病综合征、神经元缺陷和肾上腺功能不全，但其发病机制仍不清楚。在本报告中，我们描述了SGPL1基因型、诊断年龄和患者结果之间的相关性。维生素 B6 是 SPL 的辅助因子。 B6 补充剂可以通过克服不良的结合动力学并促进突变 SPL 蛋白的正确折叠和稳定性来帮助一些 SPLIS 患者。然而，这种方法仍然仅限于具有易感等位基因的患者。基因治疗代表了针对携带 B6 无反应错义突变、截短、缺失和剪接位点突变的 SPLIS 患者的潜在靶向治疗。当用腺相关病毒（AAV）介导的SGPL1基因疗法治疗 SPLIS 模型的Sgpl1敲除 (SPL ^KO ) 小鼠时，与未经治疗的 SPL ^KO小鼠相比，它们的存活率、肾脏和神经功能均显示出显着改善。因此，基因疗法作为一种普遍的、潜在的 SPLIS 治疗方法似乎很有前景。