Abstract：
Congenital disorders of glycosylation (CDG) are a group of rare, often multi-systemic genetic disorders that result from disturbed protein and lipid glycosylation. SSR4-CDG is an ultra-rare, comparably mild subtype of CDG, presenting mostly in males. It is caused by pathogenic variants in the SSR4 gene, which is located on the X chromosome. SSR4 (signal sequence receptor protein 4) is a subunit of the translocon-associated protein (TRAP) complex, a structure that is needed for the translocation of proteins across the ER membrane. A deficiency of SSR4 leads to disturbed N-linked glycosylation of proteins in the endoplasmic reticulum. Here, we review the most common clinical, biochemical and genetic features of 18 previously published individuals and report four new cases diagnosed with SSR4-CDG, including the first adult affected by this disorder. Based on our review, developmental delay, speech delay, intellectual disability, muscular hypotonia, microcephaly and distinct facial features are key symptoms of SSR4-CDG that are present in all affected individuals. Although these symptoms overlap with many other neurodevelopmental disorders, their combination with additional clinical features, and a quite distinguishable facial appearance of affected individuals make this disorder a potentially recognizable type of CDG. Additional signs and symptoms include failure to thrive, feeding difficulties, connective tissue involvement, gastrointestinal problems, skeletal abnormalities, seizures and, in some cases, significant behavioral abnormalities. Due to lack of awareness of this rare disorder, and since biochemical testing can be normal in affected individuals, most are diagnosed through genetic studies, such as whole exome sequencing. With this article, we expand the phenotype of SSR4-CDG to include cardiac symptoms, laryngeal abnormalities, and teleangiectasia. We also provide insights into the prognosis into early adulthood and offer recommendations for adequate management and care. We emphasize the great need for causal therapies, as well as effective symptomatic therapies addressing the multitude of symptoms in this disease. In particular, behavioral problems can severely affect quality of life in individuals diagnosed with SSR4-CDG and need special attention. Finally, we aim to improve guidance and education for affected families and treating physicians and create a basis for future research in this disorder.
摘要：
先天性糖基化障碍（CDG）是一组罕见的，通常是由蛋白质和脂质糖基化紊乱引起的多系统遗传疾病。SSR4-CDG是一种非常罕见的，相对温和的CDG亚型，主要表现在男性身上。它是由SSR4基因的致病变异引起的，它位于X染色体上。SSR4（信号序列受体蛋白4）是转位相关蛋白（TRAP）复合物的一个亚基，蛋白质跨内质网膜易位所需的结构。SSR4的缺乏导致内质网中蛋白质的N-连接糖基化受到干扰。这里,我们回顾了最常见的临床，18个先前发表的个体的生化和遗传特征，并报告了4例新诊断为SSR4-CDG的病例，包括第一个受这种疾病影响的成年人。根据我们的评论，发育迟缓,说话延迟,智力残疾,肌张力减退,小头症和独特的面部特征是SSR4-CDG的关键症状，存在于所有受影响的个体中。尽管这些症状与许多其他神经发育障碍重叠，它们与其他临床特征的结合，并且受影响个体的面部外观非常可区分，使这种疾病成为潜在可识别的CDG类型。其他体征和症状包括无法茁壮成长，喂养困难，结缔组织受累，肠胃问题,骨骼异常,癫痫发作和,在某些情况下,显著的行为异常。由于缺乏对这种罕见疾病的认识，由于生化检测在受影响的个体中可能是正常的，大多数是通过基因研究诊断的，如全外显子组测序。有了这篇文章,我们扩大了SSR4-CDG的表型，包括心脏症状，喉异常,和远端血管扩张.我们还提供对成年早期预后的见解，并提供适当的管理和护理建议。我们强调非常需要因果疗法，以及解决这种疾病的多种症状的有效对症疗法。特别是,行为问题可严重影响SSR4-CDG患者的生活质量,需要特别关注.最后,我们的目标是改善对受影响家庭和治疗医生的指导和教育,并为该疾病的未来研究奠定基础.
