第十二届北京罕见病学术大会暨2024京津冀罕见病学术大会（109）

Xiaona Fu^1，2， KaiLi Zhang³， Bingbing Jia¹， Wenjun Wang⁴， Lu Wang¹

 Lin Ge¹， Hui Xiong^{1，2， *}

¹ Department of Neurology， Beijing Children’s Hospital， Capital Medical University， National Center for Children’s Health， Beijing

²Laboratory for Clinical Medicine， Capital Medical University

³Department of Neurology， Anhui Provincial Children＇s Hospital

⁴Beijing Junfeix Technology Co.， Ltd.

^*Correspondence:

Hui Xiong

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. Specific gain-of-function mutations in SPTLC1 and SPTLC2 have been implicated in juvenile ALS， disrupting the regulation of serine palmitoyltransferase (SPT) and leading to excessive sphingolipid production and neurodegeneration. Up to date， there has no SPTLC2 related case report in China.

Case Report: We report a case of a 6-year-and-7-month-old male with childhood-onset ALS due to a novel de novo variant in SPTLC2 (c.197T>G， p.Thr66Arg). The patient presented with delayed motor developmental delay with regression， muscle atrophy， and scoliosis， among other symptoms consistent with the diagnosis of ALS. Trio whole-exome sequencing confirmed the variant， which was associated with altered hydrogen bonding in the SPT complex， potentially disrupting sphingolipid homeostasis.

Results: Analysis of sphingolipid levels using ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS) revealed distinct metabolic profiles among the patient， a SPTLC1-HSAN patient， and control subjects. The SPTLC2-ALS patient exhibited higher concentrations of sphingomyelin and ceramide， while the SPTLC1-HSAN patient showed elevated levels of 1-deoxydihydroceramide.

Discussion: This case supports the association of SPTLC2 variants with childhood-onset ALS due to dysregulated sphingolipid metabolism. Potential therapeutic strategies include sphingolipid metabolism modulation， gene therapy， and symptomatic treatment， though further research and clinical trials are necessary.

Conclusion: The novel de novo SPTLC2 variant contributes to childhood-onset ALS in Chinese patient， highlighting the importance of sphingolipid metabolism in ALS pathogenesis and the need for targeted diagnostic and therapeutic approaches.