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Abstract：
Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.
摘要：
Mitofusin-2（MFN2）是真核生物细胞中两种广泛表达的同源蛋白之一，在线粒体融合中起关键作用。MFN2突变（最常见的常染色体显性）导致Charcot-Marie-Tooth病2A型（CMT2A），CMT最常见的轴突形式，具有显著的等位基因异质性。以前，中等大小,CMT2A的横断面基因型表型研究描述了该疾病的表型谱，但是缺乏纵向自然史研究。在这项对196例显性和常染色体隐性CMT2A患者进行的大型多中心前瞻性队列研究中，我们对CMT2A患者的基线特征和描述自然史的纵向数据(1-2年)进行了深入的基因型-表型研究.常染色体显性遗传CMT2A的儿童期发作是显著疾病严重程度的最具预测性的标志物,并且与疾病持续时间无关。与成人发作常染色体显性遗传CMT2A相比，它与踝足矫形器的使用率高得多有关，全职使用轮椅，灵活性困难，并且在初始评估时也有显着较高的CMT检查评分（CMTESv2）和CMT神经病变评分（CMTNSv2）。使用CMTESv2及其Rasch加权对应物分析纵向数据，CMTESv2-R,表明超过1年，常染色体显性遗传CMT2A中的CMTESv2显着增加（平均变化0.84±2.42；双尾配对t检验P=0.039）。此外，2年后,CMTESv2(平均变化0.97±1.77;双尾配对t检验P=0.003)和CMTESv2-R(平均变化1.21±2.52;双尾配对t检验P=0.009)均显著增加,标准化反应均值分别为0.55和0.48.在儿科CMT2A人群中（常染色体显性和常染色体隐性CMT2A组合在一起），CMT儿科量表在1年以上(平均变化2.24±3.09;双尾配对t检验P=0.009)和2年以上(平均变化4.00±3.79;双尾配对t检验P=0.031)均显著增加,标准化应答均值分别为0.72和1.06.这项对迄今为止报道的最大CMT2A队列的横截面和纵向研究为变异解释提供了指导。告知预后,并提供指导临床试验设计的自然历史数据.
