纯合SLC52A2 p.Pro134Leu的纵向核黄素反应：一个土耳其家系中的核黄素转运体缺乏症2型

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中文摘要

核黄素转运体缺乏症（RTD）是一种罕见但可治疗的常染色体隐性神经退行性疾病，由SLC52A2（RTD2）或SLC52A3（RTD3）双等位基因变异引起。它通常表现为运动神经元病和感音神经性听力损失。大剂量核黄素有益，但不能阻止疾病进展，且治疗反应的决定因素仍不清楚。描述一个携带纯合SLC52A2 p.Pro134Leu的土耳其家系的表型和纵向核黄素反应，并将可逆性与治疗时机相关联。所有四例患者均接受了临床、神经生理学、听力学、眼科和神经影像学评估；该变异通过全外显子组测序鉴定，并通过Sanger测序和家系分离确认。患者接受大剂量核黄素治疗并随访五年。核黄素反应与症状发作至治疗之间的间隔相关。病例1在发病后八个月接受治疗，实现了完全临床恢复，神经传导改善，神经源性改变在一年内消退。病例2在发病后约十三年接受治疗，表现为临床稳定，但两年后电生理无改善；她还患有视神经萎缩和重度听力损失。病例3和4通过级联筛查发现，并在症状前接受治疗；两人检查均有细微体征，基线电生理正常，约四年后仍无症状，神经传导研究和针极肌电图正常。在考虑评估时年龄后，家系内表型变异性有限，仅限于初始表现和早期听力学受累。在病例2中，最早的听力损失仅限于8000 Hz，后来扩展到言语频率。这是第二个独立的携带p.Pro134Leu的土耳其家系，符合区域性奠基者等位基因或复发性突变。在这个家系中，核黄素治疗的结果与开始治疗的早晚相关。级联筛查发现了处于亚临床、电生理完整阶段的受累亲属，高频测听在听力损失影响言语频率之前就检测到了它。

英文摘要

Riboflavin transporter deficiency (RTD) is a rare but treatable autosomal recessive neurodegenerative disorder caused by biallelic variants in SLC52A2 (RTD2) or SLC52A3 (RTD3). It typically presents with motor neuronopathy and sensorineural hearing loss. High-dose riboflavin is beneficial but does not halt disease progression, and the determinants of treatment response remain unclear. To describe the phenotype and longitudinal riboflavin response in a Turkish kindred with homozygous SLC52A2 p.Pro134Leu, and to relate reversibility to the timing of treatment. All four patients underwent clinical, neurophysiological, audiological, ophthalmological, and neuroimaging evaluations; the variant was identified by whole-exome sequencing and confirmed by Sanger sequencing and family segregation. Patients received high-dose riboflavin and were followed for five years. The response to riboflavin was related to the interval between symptom onset and treatment. Case 1, treated eight months after onset, achieved complete clinical recovery, with improved nerve conduction and resolution of neurogenic changes within a year. Case 2, treated approximately thirteen years after onset, showed clinical stabilization but no electrophysiological improvement after two years; she also had optic atrophy and severe hearing loss. Cases 3 and 4 were identified by cascade screening and treated presymptomatically; both had subtle signs on examination and normal baseline electrophysiology, and they remain asymptomatic with normal nerve conduction studies and needle EMG after approximately four years. Once age at assessment was taken into account, phenotypic variability within the family was limited, confined to the initial presentation and to early audiological involvement. In Case 2, the earliest hearing loss was confined to 8000 Hz and later extended to the speech frequencies. This is the second independent Turkish family with p.Pro134Leu, consistent with either a regional founder allele or a recurrent mutation. In this family, the outcome of riboflavin therapy tracked how early it was started. Cascade screening revealed affected relatives at a subclinical, electrophysiologically intact stage, and high-frequency audiometry detected hearing loss before it affected speech frequencies.