Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.
Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.
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DOI：
10.1002/mus.27113
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发表时间：
2021-03
期刊：
影响因子：
3.4
通讯作者：
Bhattaram VA
中科院分区：
文献类型：
--
作者：
Haber G;Conway KM;Paramsothy P;Roy A;Rogers H;Ling X;Kozauer N;Street N;Romitti PA;Fox DJ;Phan HC;Matthews D;Ciafaloni E;Oleszek J;James KA;Galindo M;Whitehead N;Johnson N;Butterfield RJ;Pandya S;Venkatesh S;Bhattaram VA
在诊断为儿童期发作的肌营养不良蛋白病的男性中，量化基因突变和失肌萎缩（LoA）之间的关联对于理解疾病进展的变化很重要，并且可能在临床试验设计中有用。分析了来自肌营养不良监测、跟踪和研究网络的遗传和临床数据，这些数据来自1982-2011年出生和诊断的358名男性。LoA被定义为独立自主性终止的年龄。遗传突变由总体类型（缺失/重复/点突变）和缺失中的那些适合外显子跳跃疗法（外显子8、20、44-46、51-53）和另一组来定义。采用考克斯比例风险回归模型估计风险比（HR）和95%置信区间（CI）。突变类型不能预测至LoA的时间。在控制皮质类固醇激素的情况下，外显子8（HR=0.22，95%CI = 0.08，0.63）和44（HR=0.30，95%CI = 0.12，0.78）与迟发LOA相关。延迟LoA在男性突变服从外显子跳跃治疗是与以前的研究一致。这些发现表明，包括外显子8和44可跳过男性的临床试验应考虑随机化前的突变信息。
Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982–2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44–46, 51–53) and another group. Cox proportional hazards regression modeling was used to estimate hazards ratios (HR) and 95% confidence intervals (CI). Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR=0.22; 95% CI=0.08,0.63) and 44 (HR=0.30; 95% CI=0.12,0.78) were associated with delayed LOA compared to other exon deletions. Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.
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影响因子：
11.2
作者：
Flanigan, Kevin M.;Ceco, Ermelinda;Lamar, Kay-Marie;Kaminoh, Yuuki;Dunn, Diane M.;Mendell, Jerry R.;King, Wendy M.;Pestronk, Alan;Florence, Julaine M.;Mathews, Katherine D.;Finkel, Richard S.;Swoboda, Kathryn J.;Gappmaier, Eduard;Howard, Michael T.;Day, John W.;McDonald, Craig;McNally, Elizabeth M.;Weiss, Robert B.
通讯作者：
Weiss, Robert B.
影响因子：
64.8
作者：
KUNKEL, LM;HEJTMANCIK, JF;FRANCKE, U
通讯作者：
FRANCKE, U
影响因子：
6
作者：
Magri, Francesca;Govoni, Alessandra;Comi, Giacomo Pietro
通讯作者：
Comi, Giacomo Pietro
影响因子：
1.9
作者：
Kim, Sunkyung;Campbell, Kimberly A.;Valdez, Rodolfo
通讯作者：
Valdez, Rodolfo
影响因子：
1.9
作者：
KRAMER, CY
通讯作者：
KRAMER, CY