Data_Sheet_1_NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum.docx

Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations.
Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016–2020).
Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo–low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males.
Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/– congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets.

背景：NANS-CDG是一种新近被报道的先天性糖基化障碍（congenital disorder of glycosylation, CDG），由编码从头唾液酸合成关键酶的NANS基因发生双等位遗传变异所致。糖缀合物末端的唾液酸在大脑发育、骨骼发育等诸多生物学过程中发挥核心调控作用。本研究为一项观察性队列研究，旨在明确该疾病的遗传、生化及临床表型，并评估其潜在关联。
方法：本研究回顾性提取并分析了2016—2020年间的临床与实验室病历资料，涵盖遗传、生化及临床相关数据。
结果：本研究纳入了转诊至拉德堡德大学医学中心（Radboudumc）CDG专家中心的9例NANS-CDG患者（来自9个家庭，涉及6个国家）。表型分型确认了该病的标志性特征：包括全面性智力发育障碍（intellectual developmental disorder, IDD）（9/9，100%）、面部畸形（9/9，100%）、神经功能损害（9/9，100%）、身材矮小（8/9，89%）、骨骼发育不良（8/9，89%）及肢体短小（8/9，89%）。本次研究新发现的表型包括：眼科异常（6/9，67%）、透明隔异常（6/9，67%）、（进行性）脑萎缩与脑室扩张（5/9，56%）、胃肠功能紊乱（5/9，56%）、血小板减少症（5/9，56%）及低密度脂蛋白胆固醇降低（4/9，44%）。生化检测显示，尿液中N-乙酰甘露糖胺（N-acetylmannosamine, ManNAc）排泄量升高具有诊断特异性，其浓度与临床严重程度呈显著正相关。遗传学分析共鉴定出8种全新的NANS基因变异。3例重症患者携带完全一致的复合杂合致病性变异，其中1例接受了口服唾液酸的实验性产前与产后联合治疗，该患者的精神运动发育水平显著优于另外2例基因型相同的男性患者。
结论：对于存在智力发育障碍、身材矮小伴肢体短小、面部畸形、神经功能损害，以及脑影像学提示透明隔异常伴/不伴先天性与神经退行性病变的患者，应考虑开展ManNAc筛查，以实现精准诊断并辅助预后评估。个体化管理策略包括：完善遗传咨询、为胃肠功能紊乱、血小板减少症及癫痫患者提供恰当支持与针对性治疗，以及为认知与躯体功能障碍患者提供康复服务。基于口服唾液酸实验性治疗的短期积极疗效，我们已启动针对4例患者的该干预方案，并将对其神经、全身及生长结局进行标准化随访。目前相关研究仍在进行中，旨在阐明疾病病理生理学机制并发掘全新治疗靶点。