Yoldaş Çelik Merve, Köşeci Burcu, Burgaç Ezgi, Yararbaş Kanay
Adana City Training and Research Hospital, Department of Pediatric Metabolism, Adana, Turkey.
Demiroglu Bilim University Faculty of Medicine, Department of Medical Genetics, Istanbul, Turkey.
Mol Genet Metab Rep. 2025 Apr 29;43:101225. doi: 10.1016/j.ymgmr.2025.101225. eCollection 2025 Jun.
GM2 activator deficiency (AB variant of GM2 gangliosidosis) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic GM2A mutations. The loss of a functional GM2 activator protein disrupts GM2 ganglioside degradation, leading to progressive neurodegeneration. Although it shares clinical features with Tay-Sachs disease, GM2 activator deficiency remains a genetically and biochemically distinct disorder, with limited genotype-phenotype correlation due to the small number of reported cases. This report presents a 33-month-old male with an infantile-onset phenotype, characterized by nystagmus, axial hypotonia, hyperacusis, and bilateral cherry-red spots. Genetic analysis identified a homozygous likely pathogenic c.262_264del (p.Lys88del) mutation, reinforcing its potential association with early disease onset. His clinical course was marked by progressive neurodegeneration, recurrent pulmonary infections, and severe feeding difficulties requiring gastrostomy placement. In addition, previously published cases were reviewed to provide insights into the phenotypic spectrum, age of onset, and key clinical characteristics of GM2 activator deficiency. Among the 22 reported cases, 77.3 % exhibited an infantile-onset phenotype, while 18.2 % and 4.5 % had juvenile and adult-onset forms, respectively. Notably, cherry-red spots and hyperacusis were present in 94.1 % and 82.4 % of infantile cases but were strikingly absent in later-onset phenotypes. This case report, supplemented by a literature review, offers a comprehensive overview of GM2 activator deficiency and underscores the importance of early molecular diagnosis in suspected cases.
GM2激活剂缺乏症（GM2神经节苷脂沉积症AB变异型）是一种极其罕见的常染色体隐性溶酶体贮积症，由致病性GM2A突变引起。功能性GM2激活蛋白的缺失会破坏GM2神经节苷脂的降解，导致进行性神经变性。尽管它与泰-萨克斯病有共同的临床特征，但GM2激活剂缺乏症在遗传和生化方面仍然是一种独特的疾病，由于报告的病例数量较少，基因型与表型的相关性有限。本报告介绍了一名33个月大的男性，具有婴儿期发病的表型，其特征为眼球震颤、轴性肌张力减退、听觉过敏和双侧樱桃红斑。基因分析确定了一个纯合的可能致病性c.262_264del（p.Lys88del）突变，加强了其与疾病早期发作的潜在关联。他的临床病程以进行性神经变性、反复肺部感染和严重喂养困难（需要放置胃造口术）为特征。此外，还对先前发表的病例进行了回顾，以深入了解GM2激活剂缺乏症的表型谱、发病年龄和关键临床特征。在22例报告病例中，77.3%表现为婴儿期发病的表型，而18.2%和4.5%分别为青少年期和成人期发病形式。值得注意的是，94.1%的婴儿期病例出现樱桃红斑和听觉过敏，而在晚发型表型中则明显没有。本病例报告辅以文献综述，全面概述了GM2激活剂缺乏症，并强调了对疑似病例进行早期分子诊断的重要性。
