目的:GM2神经节苷脂,一组常染色体隐性神经变性溶酶体贮积症,由β-己糖胺酶(HEX)缺乏引起,以GM2神经节苷脂为主要底物。历史上,GM2神经节苷脂已被归类为婴儿,少年,和迟发性形式。随着疾病改善治疗试验的出现,需要对疾病过程有更细粒度的了解。
方法:我们的目的是在儿童和成人患者的多中心队列中绘制GM2神经节剂量的临床病程图并对其进行分层。根据发病年龄和诊断年龄对患者进行分层。对所得的2个GM2疾病集群进行了深入的表征,以了解各自的疾病特征(详细的标准化临床,实验室,和MRI评估)和疾病演变。
结果:在21例GM2神经节苷脂病患者中(17Tay-Sachs,2GM2激活剂缺乏症,2桑霍夫病),区分了2个疾病簇:早期发作和早期诊断簇(I型;n=8,包括激活剂缺乏症和Sandhoff病)和发作非常可变且间隔长的簇,直到诊断(II型;n=13例)。在类型I中,发展停滞和衰退的迅速开始,痉挛,癫痫发作主导了临床表现。樱桃红点,惊吓反应,和升高的AST仅在该集群中看到。在II型中,平衡或步态问题,肌肉无力,构音障碍,精神症状是特异性和频繁的症状。眼部体征很常见,包括30%的核上垂直凝视麻痹。仅在I型中可见基底节区和核仁周围高强度的MRI受累,而II型特征性的是主要的幕下萎缩(或正常的MRI)。这些类型是,至少在某种程度上,与某些遗传变异有关。
结论:仅发病时的年龄似乎不足以充分预测GM2神经节病的不同病程,根据即将进行的试验计划的要求。我们提出了一种基于疾病发作年龄和动态的替代分类,通过临床特征和生物标志物预测,I型-早发型,快速进展集群-和II型-可变发作,缓慢进展集群。具体的诊断检查,包括GM2神经节苷脂贮积症,共济失调合并下运动神经元无力的患者应进行鉴别II型患者。
GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from β-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed.
We aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution.
In 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants.
Age at onset alone seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I-an early-onset, rapid progression cluster-and type II-a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.