大剂量核黄素对Brown-Vialetto-Van Laere综合征的显著疗效：一例病例报告

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中文摘要

背景： Brown-Vialetto-Van Laere综合征目前被归入核黄素转运体缺乏3型（RTD3）谱系，是一种罕见的遗传性神经代谢性疾病，与SLC52A3致病性变异相关。其典型表现为进行性感觉神经性听力损失、脑桥延髓功能障碍、周围神经病和呼吸系统受累。尽管临床表型具有特征性，但常规代谢和神经肌肉检查可能无阳性发现，因此诊断可能被延误。
患者主诉： 一名年轻亚洲男性因数年来进行性双侧听力损失就诊，随后出现固体和液体吞咽困难加重、对称性肢体无力、肌肉萎缩以及慢性基础上急性加重的呼吸困难。两名同胞此前在幼年出现类似的听力损害、吞咽困难、肢体无力和不明原因呼吸衰竭序列后死亡。
诊断： 神经系统检查显示舌萎缩伴肌束颤动、鱼际肌萎缩、双侧面肌无力、轻度上睑下垂、咽反射减弱和对称性肢体无力。听力测定证实双侧重度感觉神经性听力损失。神经传导检查显示以运动轴索性神经病为主，肌电图显示慢性和活动性失神经支配。重复神经刺激、脑脊液分析、磁共振成像、肌酸激酶水平和代谢检查均无阳性发现。靶向基因检测发现致病性SLC52A3变异，确诊RTD3/Brown-Vialetto-Van Laere综合征。
干预： 由于进行性呼吸功能受损且临床高度怀疑，在基因确诊前即经验性开始大剂量口服核黄素40 mg/kg/天，分3次给药。支持治疗包括营养支持和夜间双水平气道正压无创通气。
结果： 开始核黄素后患者出现显著改善。呼吸做功在数日内改善，1周内用力肺活量从预计值的35%增至50%。肢体力量改善，至8周时患者体重增加3 kg，吞咽困难稳定，经口进食改善。6个月时神经系统状态保持稳定，电生理检查未见进一步进展。核黄素耐受良好。
结论： 对于伴有延髓功能障碍、运动神经病或呼吸无力的进行性感觉神经性听力损失年轻患者，尤其当家族史提示时，应考虑RTD3。识别其特征性表型、进行靶向基因检测并及时开始大剂量核黄素，可能显著改变这种潜在可治疗疾病的临床病程。

英文摘要

RATIONALE: Brown-Vialetto-Van Laere syndrome, currently recognized within the spectrum of riboflavin transporter deficiency type 3 (RTD3), is a rare inherited neurometabolic disorder associated with pathogenic variants in SLC52A3. It typically presents with progressive sensorineural hearing loss, pontobulbar dysfunction, peripheral neuropathy, and respiratory involvement. Diagnosis may be delayed because routine metabolic and neuromuscular investigations can be unrevealing despite a characteristic clinical phenotype.
PATIENT CONCERNS: A young Asian man presented with several years of progressive bilateral hearing loss followed by worsening dysphagia to solids and liquids, symmetrical limb weakness, muscle wasting, and acute-on-chronic dyspnea. Two siblings had previously died at a young age after developing a similar sequence of hearing impairment, dysphagia, limb weakness, and unexplained respiratory failure.
DIAGNOSES: Neurological examination showed tongue atrophy with fasciculations, thenar wasting, bifacial weakness, mild ptosis, diminished gag reflex, and symmetrical limb weakness. Audiometry confirmed profound bilateral sensorineural hearing loss. Nerve conduction studies demonstrated predominantly motor axonal neuropathy, while electromyography showed chronic and active denervation. Repetitive nerve stimulation, cerebrospinal fluid analysis, magnetic resonance imaging, creatine kinase levels, and metabolic investigations were unrevealing. Targeted genetic testing detected pathogenic SLC52A3 variants, confirming RTD3/ Brown-Vialetto-Van Laere syndrome.
INTERVENTIONS: High-dose oral riboflavin was initiated empirically at 40 mg/kg/day in 3 divided doses before genetic confirmation because of progressive respiratory compromise and strong clinical suspicion. Supportive management included nutritional support and nocturnal noninvasive ventilation with bilevel positive airway pressure.
OUTCOMES: The patient showed marked improvement after riboflavin initiation. Respiratory effort improved within several days, and forced vital capacity increased from 35% to 50% of predicted within 1 week. Limb strength improved, and by 8 weeks the patient had gained 3 kg with stabilization of dysphagia and improved oral intake. At 6 months, neurological status remained stable without further electrophysiological progression. Riboflavin was well tolerated.
LESSONS: RTD3 should be considered in young patients with progressive sensorineural hearing loss associated with bulbar dysfunction, motor neuropathy, or respiratory weakness, particularly when family history is suggestive. Recognition of the characteristic phenotype, targeted genetic testing, and prompt initiation of high-dose riboflavin may substantially alter the clinical course of this potentially treatable disorder.