GM1 Gangliosidosis-A Mini-Review.
GM1 Gangliosidosis-A Mini-Review.
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DOI：
10.3389/fgene.2021.734878
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发表时间：
2021
影响因子：
3.7
通讯作者：
Stepien KM
中科院分区：
文献类型：
--
作者：
Nicoli ER;Annunziata I;d'Azzo A;Platt FM;Tifft CJ;Stepien KM
GM1神经节脂质沉积症是由编码β-半乳糖苷酶的GLB1基因突变引起的进行性神经躯体溶酶体贮积症。β-半乳糖苷酶活性的缺失或降低导致含有β-半乳糖的糖缀合物，包括鞘糖脂（GSL） gm1 -神经节苷脂在神经元组织中的积累。根据临床症状的发病年龄，gm1 -神经节脂质沉积症分为三种形式[I型（婴儿），II型（婴儿晚期和青少年）和III型（成人）]，尽管该疾病实际上是一个连续体，仅部分与残留酶活性水平相关。严重的神经认知能力下降是I型和II型疾病的特征，并与过早死亡有关。文献报道的大多数致病β-半乳糖苷酶突变聚集在GLB1基因的2、6、15和16外显子上。到目前为止，已经描述了261种致病变异，错义/无义突变是最普遍的。利用不同的Glb1小鼠基因座靶向策略，文献中报道了五种gm1 -神经节脂质沉积症小鼠模型。个体模型在临床、生化、病理体征和症状的发病年龄以及总体寿命方面有所不同。然而，它们确实具有gm1神经节脂质病最严重形式的主要异常和神经系统症状特征。这些小鼠模型已被用于研究致病机制、识别生物标志物和评估治疗策略。三项GLB1基因治疗试验目前正在招募I型和II型患者（NCT04273269、NCT03952637和NCT04713475）， II型和III型患者正在招募一项使用葡萄糖神经酰胺合成酶抑制剂venglustat （NCT04221451）的试验。
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).
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