Background

Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic.

Scope of review

This review covers the latest advances in the search for a treatment for PMM2-CDG.

Major conclusions

Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins.

General significance

The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.

中文翻译：

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新的和潜在的治疗PMM2-CDG的策略。

背景

PMM2基因中的突变会导致磷酸甘露突变酶2缺乏症（PMM2; MIM＃212065），表现为先天性糖基化疾病（PMM2-CDG）。突变的PMM2导致Man-6-P向Man-1-P的转化减少，这导致鸟嘌呤5'-二磷酸-D-甘露糖浓度低，这是核苷酸寡糖，对蛋白质寡糖链的构建至关重要。迄今为止，唯一的治疗选择是预防和对症治疗。

审查范围

这篇综述涵盖了寻找PMM2-CDG治疗方法的最新进展。

主要结论

已经提出了基于增加Man-1-P水平的治疗方法，以及施用不同的甘露糖衍生物，采用酶抑制剂或改用药物来增加GDP-Man的合成。目前正在临床上使用一种单一的可改型药物，该药物可以缓解与该疾病有关的严重神经系统症状。关于使用药理伴侣蛋白和/或蛋白调节剂来增加亚型PMM2突变蛋白的浓度，也存在概念证明。

一般意义

讨论了发现治疗这种孤儿疾病的药物所面临的持续挑战。