Multiple phenotypes in phosphoglucomutase 1 deficiency.
Multiple phenotypes in phosphoglucomutase 1 deficiency.
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DOI：
10.1056/nejmoa1206605
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发表时间：
2014-02-06
期刊：
影响因子：
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通讯作者：
Marquardt T
中科院分区：
文献类型：
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作者：
Tegtmeyer LC;Rust S;van Scherpenzeel M;Ng BG;Losfeld ME;Timal S;Raymond K;He P;Ichikawa M;Veltman J;Huijben K;Shin YS;Sharma V;Adamowicz M;Lammens M;Reunert J;Witten A;Schrapers E;Matthijs G;Jaeken J;Rymen D;Stojkovic T;Laforêt P;Petit F;Aumaître O;Czarnowska E;Piraud M;Podskarbi T;Stanley CA;Matalon R;Burda P;Seyyedi S;Debus V;Socha P;Sykut-Cegielska J;van Spronsen F;de Meirleir L;Vajro P;DeClue T;Ficicioglu C;Wada Y;Wevers RA;Vanderschaeghe D;Callewaert N;Fingerhut R;van Schaftingen E;Freeze HH;Morava E;Lefeber DJ;Marquardt T
先天性糖基化障碍是导致糖蛋白产生受损的遗传综合征。我们评估了患有新型隐性糖基化疾病的患者，其临床表现包括肝病、双悬雍垂、恶性高热、低促性腺激素性性腺功能减退、生长迟缓、低血糖、肌病、扩张型心肌病和心脏骤停。全外显子测序后的纯合性定位被用来确定两个兄弟姐妹中磷酸葡萄糖变位酶1（PGM 1）基因的突变。测序在其他15个家庭中发现了额外的突变。在细胞提取物上测定磷酸葡萄糖变位酶1酶活性。进行糖基化效率分析和糖代谢产物的定量研究。研究了成纤维细胞培养物中的半乳糖补充和患者的饮食补充，以确定对糖基化的影响。所有患者的磷酸葡萄糖变位酶1酶活性均显著降低。转铁蛋白的质谱显示完整N-聚糖的损失和缺乏半乳糖的截短聚糖的存在。补充半乳糖的成纤维细胞显示蛋白质糖基化的恢复和糖原积累的证据。饮食补充半乳糖在6例患者中导致的变化提示临床改善。一项新的筛查试验显示，患者和对照组之间有很好的区分。磷酸葡萄糖变位酶1缺乏症，以前被鉴定为糖原病，也是一种先天性糖基化疾病。补充半乳糖导致细胞和患者中糖基化指数的生化改善，补充复合碳水化合物稳定血糖。一种新的筛查方法已经开发出来，但尚未得到验证。（由荷兰科学研究组织和其他组织资助。
Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.)