SLC52A2相关核黄素转运体缺乏症在非孤立性听神经病中的表现：来自中国队列的证据及全球变异综述

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中文摘要

背景/目的： 核黄素转运体缺乏症2型（RTD2）由SLC52A2双等位基因致病变异引起，是一种可治疗的神经退行性疾病，听神经病可能是其早期表现。本研究描述了SLC52A2相关RTD2的临床和遗传谱，重点关注听力学表现及已报道变异谱的地域差异。方法：我们在一个多中心队列中筛查临床诊断为听神经病的无亲缘关系先证者是否存在SLC52A2相关疾病。回顾了临床、听力学、遗传学、治疗和随访数据。检索PubMed、Web of Science和Embase自建库至2026年2月，以总结已报道的SLC52A2变异。结果：4例患者携带8个不同的SLC52A2变异，其中4个既往未见报道。听力学检查确定了听神经病表型，发病年龄在0.5至4岁之间，严重程度从轻度或中度到极重度不等。在2例患者中，听力损失是首发或同时出现的初始表现。核黄素治疗改善了贫血、共济失调、肌力和运动功能，而已确立的听觉和视觉损害恢复有限。中国队列显示SLC52A2变异分布分散，未在已知热点处聚集。在全球数据集中，p.G306R是最常见的变异，占已报道变异等位基因的41.6%（74/178）。结论：对于早发性或进行性听神经病并伴多系统表现的儿童，应考虑SLC52A2相关RTD2。早期分子诊断可能有助于在不可逆神经损伤发生前及时给予核黄素治疗。这4个既往未报道的变异扩展了SLC52A2变异谱，而已发表病例中识别出的地域模式需要在更大队列中验证。

英文摘要

Background/Objectives: Riboflavin transporter deficiency type 2 (RTD2), caused by biallelic pathogenic variants in SLC52A2, is a treatable neurodegenerative disorder in which auditory neuropathy may be an early manifestation. This study characterized the clinical and genetic spectrum of SLC52A2-related RTD2, with emphasis on auditory findings and geographic variation in the reported variant spectrum. Methods: We screened unrelated probands with clinically diagnosed auditory neuropathy from a multicenter cohort for SLC52A2-related disease. Clinical, audiological, genetic, treatment, and follow-up data were reviewed. PubMed, Web of Science, and Embase were searched from inception through Feb 2026 to summarize reported SLC52A2 variants. Results: Four patients carried eight distinct SLC52A2 variants, four of which were previously unreported. Audiological testing identified an auditory neuropathy phenotype, with onset between 0.5 and 4 years of age and severity ranging from mild or moderate to profound. In two patients, hearing loss was the first or a concurrent initial manifestation. Riboflavin treatment improved anemia, ataxia, muscle strength, and motor function, whereas established auditory and visual impairment showed limited recovery. The Chinese cohort showed a dispersed variant distribution across SLC52A2, without clustering at known hotspots. In the global dataset, p.G306R was the most frequent variant, accounting for 41.6% (74/178) of reported variant alleles. Conclusions: SLC52A2-related RTD2 should be considered in children with early-onset or progressive auditory neuropathy and multisystem manifestations. Early molecular diagnosis may permit timely riboflavin treatment before irreversible neural injury develops. The four previously unreported variants expand the SLC52A2 variant spectrum, while the geographic patterns identified in published cases require validation in larger cohorts.