Vaes Laurien, Tiller George E, Pérez Belén, Boyer Suzanne W, Berry Susan A, Sarafoglou Kyriakie, Morava Eva
Faculty of Medicine KU Leuven Leuven Belgium.
Department of Genetics Kaiser Permanente Los Angeles California USA.
JIMD Rep. 2020 Apr 28;54(1):16-21. doi: 10.1002/jmd2.12122. eCollection 2020 Jul.
Phosphomannomutase 2 deficiency PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy.
Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG.A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG.
Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counseling.
磷酸甘露糖变位酶2缺乏症（PMM2-CDG）影响糖基化途径，如N-糖基化途径，导致多种蛋白质功能丧失。这种疾病会导致多系统受累，患者之间存在高度变异性。PMM2-CDG是一种常染色体隐性疾病，可由遗传两个致病变异、新发突变或单亲二体引起。
我们的患者在幼年时就出现了多系统症状，包括发育迟缓、共济失调和癫痫发作。直到31岁重新进行基因检测时才确诊。患者被诊断为16号染色体完全母源混合杂合/等二体，携带一个纯合致病变异PMM2（p.Phe119Leu），导致PMM2-CDG。文献综述显示，有8例单亲二体是先天性糖基化障碍（CDG）的潜在病因，其中4例为PMM2-CDG。
由于PMM2变异纯合子的发生率很低，我们建议对每例分离情况不符的纯合PMM2-CDG患者进行进一步检查。这些检查包括检测单亲二体或两个等位基因之一的缺失，因为这将对遗传咨询中的复发风险产生影响。
