获批治疗时代的胸苷激酶2缺乏症：从诊断到跨疾病谱系的证据

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中文摘要

胸苷激酶2缺乏症（TK2d）是一种超罕见常染色体隐性线粒体DNA（mtDNA）维持障碍，由核基因TK2的致病性变异引起。TK2活性丧失破坏线粒体内脱氧核苷酸池，损害mtDNA复制，导致一系列定量（mtDNA耗竭）和定性（多重缺失）改变，其严重程度是预后的关键决定因素。临床上，TK2d表现为连续的临床表型谱，从快速进展的婴儿型疾病到成人起病型，主要表现为进行性肌病伴早期延髓和呼吸受累，这是发病和死亡的主要驱动因素，总体严重程度与发病年龄呈负相关。严重早发型病例可能出现中枢神经系统受累，而除此之外肌肉外表现有限，整个疾病谱系中描述了感音神经性听力损失和亚临床轴索性感觉神经病。循环生物标志物，尤其是GDF-15，支持诊断、与疾病严重程度相关并显示随治疗出现的动态变化；血清肌酐、肌肉MRI脂肪分数和用力肺活量进一步有助于预后分层。口服多西胞苷和多西核糖胸苷补充治疗最近于2025年获FDA、2026年获EMA批准用于症状发作≤12岁的患者，是TK2d首个疾病修饰疗法，显示出显著的生存获益、疾病进展稳定和运动功能部分恢复。成人患者的证据仍然有限且多为回顾性，凸显了开展专门前瞻性研究并使用对缓慢进展表型敏感结局指标的必要性。

英文摘要

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder caused by pathogenic variants in the nuclear TK2 gene. Loss of TK2 activity disrupts intramitochondrial deoxynucleotide pools, impairing mtDNA replication and resulting in a spectrum of quantitative (mtDNA depletion) and qualitative (multiple deletions) alterations whose severity is a key determinant of prognosis. Clinically, TK2d presents as a continuous phenotypic spectrum, from rapidly progressive infantile disease to adult-onset forms, predominantly manifesting as progressive myopathy with early bulbar and respiratory involvement, the principal drivers of morbidity and mortality, with overall severity inversely correlated with age at onset. Central nervous system involvement may occur in severe early-onset cases, whilst extramuscular manifestations are otherwise limited, with sensorineural hearing loss and subclinical axonal sensory neuropathy described across the spectrum. Circulating biomarkers, particularly GDF-15, support diagnosis, correlate with disease severity and show dynamic changes with treatment; serum creatinine, muscle MRI fat fraction and forced vital capacity further contribute to prognostic stratification. Oral supplementation with doxecitine and doxribtimine, recently approved by the FDA (2025) and EMA (2026) for patients with symptom onset ≤ 12 years, represents the first disease-modifying therapy for TK2d, demonstrating marked survival benefit, stabilisation of disease progression and partial recovery of motor function. Evidence in adult patients remains limited and largely retrospective, underscoring the need for dedicated prospective studies with outcome measures sensitive to slowly progressive phenotypes.