D-甘露糖作为治疗褐藻糖激酶缺乏症相关先天性糖基化紊乱(FCSK-CDG)的一种新疗法

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Molecular genetics and metabolism Pub Date : 2024-05-09 DOI:10.1016/j.ymgme.2024.108488
Rodrigo Tzovenos Starosta , Angela J. Lee , Elizabeth R. Toolan , Miao He , Parith Wongkittichote , Earnest James Paul Daniel , Silvia Radenkovic , Rohit Budhraja , Akhilesh Pandey , Jaiprakash Sharma , Eva Morava , Hoanh Nguyen , Patricia I. Dickson
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引用次数: 0

摘要

导言岩藻糖激酶缺乏症相关先天性糖基化障碍(FCSK-CDG)是一种罕见的常染色体隐性遗传先天性代谢错误,其特征是由于从溶酶体排出的L-岩藻糖循环受阻,导致GDP-岩藻糖生物合成的挽救途径通量减少。迄今为止,医学文献中已描述了 5 例 FCSK-CDG 患者,其表型包括全面发育迟缓/智力障碍、肌张力低下、髓鞘异常、后眼病、生长和喂养失败、免疫缺陷和慢性腹泻,但没有明确的治疗建议。患者和方法在一名迄今未报道过的 FCSK-CDG 患者身上,我们研究了患者成纤维细胞体外蛋白质组学和糖蛋白组学,并在使用 D-甘露糖或 L-岩藻糖治疗前后进行了体内糖组学研究。随后,患者接受了850毫克/千克/天的D-甘露糖治疗,慢性腹泻症状得到缓解,口服厌恶感消失,体重增加,发育也得到了改善。血清 N-聚糖图谱显示,治疗后岩藻糖基化聚糖的丰度有所提高。结论D-甘露糖是一种很有前景的治疗 FCSK-CDG 的新方法。
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D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG)

Introduction

Fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG) is a rare autosomal recessive inborn error of metabolism characterized by a decreased flux through the salvage pathway of GDP-fucose biosynthesis due to a block in the recycling of L-fucose that exits the lysosome. FCSK-CDG has been described in 5 individuals to date in the medical literature, with a phenotype comprising global developmental delays/intellectual disability, hypotonia, abnormal myelination, posterior ocular disease, growth and feeding failure, immune deficiency, and chronic diarrhea, without clear therapeutic recommendations.

Patient and methods

In a so far unreported FCSK-CDG patient, we studied proteomics and glycoproteomics in vitro in patient-derived fibroblasts and also performed in vivo glycomics, before and after treatment with either D-Mannose or L-Fucose.

Results

We observed a marked increase in fucosylation after D-mannose supplementation in fibroblasts compared to treatment with L-Fucose. The patient was then treated with D-mannose at 850 mg/kg/d, with resolution of the chronic diarrhea, resolution of oral aversion, improved weight gain, and observed developmental gains. Serum N-glycan profiles showed an improvement in the abundance of fucosylated glycans after treatment. No treatment-attributed adverse effects were observed.

Conclusion

D-mannose is a promising new treatment for FCSK-CDG.

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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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